The coronavirus disease 2019 (COVID‐19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that the rapidly evolving coronavirus subvariants risk rendering vaccines and antibodies ineffective due to their potential to evade existing immunity, with enhanced transmission activity and higher reinfection rates that could lead to new outbreaks across the globe. The goal of viral management is to disrupt the viral life cycle as well as to relieve severe symptoms such as lung damage, cytokine storm, and organ failure. In the fight against viruses, the combination of viral genome sequencing, elucidation of the structure of viral proteins, and identifying proteins that are highly conserved across multiple coronaviruses has revealed many potential molecular targets. In addition, the time‐ and cost‐effective repurposing of preexisting antiviral drugs or approved/clinical drugs for these targets offers considerable clinical advantages for COVID‐19 patients. This review provides a comprehensive overview of various identified pathogenic targets and pathways as well as corresponding repurposed approved/clinical drugs and their potential against COVID‐19. These findings provide new insight into the discovery of novel therapeutic strategies that could be applied to the control of disease symptoms emanating from evolving SARS‐CoV‐2 variants. In this review, authors provide a comprehensive overview of various identified pathogenic targets and pathways, as well as corresponding repurposed approved/clinical drugs and their potential against COVID‐19. Moreover, authors summarizenumerous potential pathogenic targets associated with viral life cycle and virus–host cell communication, repurposed drugs and their mechanism‐of‐actions for pathogenic targets that have been vetted for safety, and repurposed drugs that are approved or clinical available for COVID‐19.And thenthe future prospects of drug repurposing strategies in discovery and development of pathogenic targets and novel medicines as well as effective therapeutics for combating COVID‐19 and other infectious diseases that are current or on the horizon are discussed.  There are the structural proteins, nonstructural proteins (nsps), and accessory proteins, which interact with numerous host cellular factors to conduct essential physiological roles.2.1.1Spike glycoprotein is the largest structural protein protruding from the surface of mature SARS‐CoV‐2 virions. It plays essential roles during the initial steps of pathogenesis, through mediating receptor recognition, cell attachment and fusion during viral infection, and these events ultimately lead to the virus entering the host cell. Some studies revealed the evolution between SARS‐CoV‐2 and SARS‐CoV with similarity in both structure and sequence; SARS‐CoV polyclonal antibodies are able to inhibit SARS‐CoV‐2 Spike‐mediated entry into cells.The surface location of the Spike glycoprotein renders it a direct target for host immune responses, making it the focus of many vaccine strategies as well as the main target of neutralizing antibodies. However, this protein is under strong selection pressure and is at high risk for undergoing mutagenesis, including mutations in the receptor binding domain (RBD) and mutations and deletions within the N‐terminal domain (NTD).2.1.2Spike proteins initiate cell entry by connecting viruses to cell membrane receptors, prior to catalyzing virus–host cell membrane fusions. ACE2 was the first receptor found for SARS‐CoV‐2 that was used to gain entry into the host cells. It has been previously shown that SARS‐CoV recognizes the entry receptor hACE2, and structural studies and biochemical experiments have also confirmed the binding of SARS‐CoV2 Spike protein to human ACE2 as the host receptor.Considering the low expression of ACE2 in the human respiratory tract and high infectivity of COVID‐19,CD147 is a transmembrane glycoprotein that has previously been reported to play a functional role in facilitating SARS‐CoV infection; it was confirmed to mediate SARS‐CoV‐2 entry by endocytosis and both loss and blocking of CD147 inhibited SARS‐CoV‐2 entry and amplification in different models.2.1.3After the Spike glycoprotein initiates infection via binding to host receptors on cell surface, the latter membrane fusion requires proteolytic cleavages at two different sites (S1 and S2) by host cell proteases of S protein to develop a conformational flexibility; these activities reveal potential drug targets.Furin‐like proteases are classified as a type I transmembrane protein and proprotein convertase that cleaves the precursors of a broad range of proteins, including cell surface receptors.The pH‐sensitive endosomal cysteine proteases CatB/L mediate the cleavage of an additional site internal to the S2 subunit of SARS‐CoV‐2 in the endosomal compartment, termed the “S2′ site,” which associates with ACE2. Membrane formation is then initiated by further release of the fusion peptide through ACE2‐mediated endocytosis.2.1.4SARS‐CoV‐2 belongs to the class of positive‐sense RNA viruses. Its genome (30 kb) encodes two type proteins: (1) the structural, Spike (S), Nucleocapsid (N), Envelope (E), and Matrix (M) and (2) the nonstructural proteins (nsp1 up to nsp16), including RdRp (NSP12).2.1.5The replicase gene is a major component of the SARS‐CoV genome that encodes two large PPs (PP1a and PP1ab), which are cleaved into 16 NSPs. There are two types of cysteine proteases that act on these PPs to release the NSPs. The C‐terminal of these PPs (PP1a) is cleaved by Mpro or 3CLpro (corresponding to NSP5), and the N‐terminal of these PPs (PP1ab) is processed by PLpro (a domain within NSP3) into functional units.Another potentially targetable SARS‐CoV‐2 protease is PLpro, which show high sequence homology (∼90%) to SARS‐CoV PLpro.Other pathogenic targets involved in the SARS‐CoV‐2 life cycle include the envelope protein, the NSP9 RNA binding protein (NSP9), and the Replicase Polyprotein 1a (RP1a), which lead to viral proliferation in host cells.2.2Drugs that have been approved for COVID‐19 therapy are currently being developed based on antiviral targets that are necessary for different stages of the viral infection cycle.2.2.1,All stages of the viral life cycle consume host resources, and cellular kinases in particular appear to be essential for the life cycle of the virus. Kinases are involved in transmission, pneumonia‐like symptoms, inflammation and fibrosis in coronavirus infection, and targeting them are now a significant effort of numerous pharmaceutical companies.ABL is a nonreceptor tyrosine kinase that is involved in cell proliferation, survival, migration and stress responses.The SFKs is a class of nonreceptor tyrosine kinases that play an important role in signal transduction, and regulate a number of biological processes that promote cell survival and motility, as well as inflammatory responses.AXL kinase is an identified host receptor of SARS‐CoV‐2 that interacts with the NTD of Spike protein.The NAK family consists of four members: (1) the adaptor‐associated kinase 1 (AAK1), (2) cyclin G‐associated kinase, (3) BMP‐2 inducible kinase (BIKE/BMP2K), and (4) serine/threonine kinase 16 (STK16), which act to regulate intracellular membrane trafficking.EGFR and its activation affect cell growth, development, and survival.SARS‐CoV‐2 relies on regulating host metabolism pathways to meet its need to produce as many virus particles as possible. Among those host signaling pathways, the phosphatidylinositol 3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) cell signaling pathway has drawn attention. The PI3K/Akt/mTOR pathway regulates and incorporates various signaling processes in cells, including cell proliferation. Recently, studies have shown that activation of the PI3K/Akt/mTOR signaling pathway is involved in the proliferation and replication of a variety of viruses, including hepatitis C virus (HCV), West Nile virus, and influenza A virus.CDKs are a family of serine/threonine kinases that include 20 members.CK2 is a highly pleiotropic and constitutively active Ser/Thr kinase that is important for cell survival, neoplasia and virus infection.The p38 MAPK signaling pathway can be triggered by diverse factors, including environmental stress, viral infection and cytokine storm. This pathway is essential for cell differentiation, apoptosis and autophagy. In SARS‐CoV‐1, p38 is directly involved in viral proliferation by inducing the receptor‐mediated endocytosis for intrusive virus.SARS‐CoV‐2‐infected patients present some common symptoms, including fever, dry cough or dyspnea. However, the severe and life‐threatening pathology, such as failure of organs and tissue injuries, are majorly due to cytokine storm resulting from a virus‐driven hyper‐inflammatory response. JAK–STAT are among a large number of pathways involved in cytokine storm triggered by SARS‐CoV‐2.GSK‐3 is a highly conserved serine/threonine kinase that plays a role in metabolism, inflammatory response, and cell proliferation.Another potential host therapeutic target is BRD2, a member of the BET  family, which can regulate gene transcription through binding acetylated histones.Additional potential kinases exist that could be explored as targets for COVID‐19 remission. For example, molecular targeting of the ataxia telangiectasia and Rad3‐related protein, which is associated with DNA‐damage response signaling pathways, has been shown to inhibit SARS‐CoV‐1, SARS‐CoV‐2, and MERS‐CoV infection.2.2.2Other potential targets associated with virus–host response have been identified in clinical studies. The complex immunopathological manifestations of COVID‐19 include lymphopenia or exhaustion , dysregulation of monocytes and macrophages (phenotypic shift and increased numbers), neutropenia , antibody‐dependent enhancement (which may enhance entry of SARS‐CoV‐2), reduced or delayed IFN‐I response  and more alarmingly, cytokine storm, characterized by increased levels of proinflammatory mediators that correlate with worse prognosis in patients with severe infection.Extensive evidence from preclinical and clinical studies suggests that cytokine storm syndrome may be an important mechanism responsible for this respiratory disorder.Therapy approaches targeting virus–host responses, including immunomodulatory therapies  may be helpful in alleviating SARS‐CoV‐2 symptoms; other options, such as stem cell‐based therapy and blood purification therapy, may also provide clinical benefit.3Drug discovery is a lengthy, complex, and costly process, from conception to availability in the market, with a high degree of uncertainty. Among different approaches that have been proven effective for combating COVID‐19, a drug repurposing strategy is a more economical and faster approach than the traditional drug discovery and development process. The concept of identifying potent molecules from drug libraries that have been approved or are in clinical trials, or compounds that have been tested against conserved targets in coronaviruses previously, has become accelerated, effective, and feasible ways to identify drugs that can prevent COVID‐19.The advent of Spike protein‐based vaccines has abated the global burden; however, they were not found to be effective against all the variants of concern due to the rapid evolution of SARS‐CoV‐2.3.1SARS‐CoV‐2 uses the spike protein to recognize human cells and induce the fusion of the viral and human cell membranes through receptor binding.3.1.1Viral replication and spread mainly relies on the interaction between the Spike protein and host cell surface receptors, thereby mediating membrane fusion and causing viral invasion. Some studies report that development of drugs, including antibodies or small molecular inhibitors that target the S protein or affect the binding of the S protein to the host cell receptor is beneficial for constraining coronavirus infection. Researchers repurposed the neutralizing antibodies from convalescent SARS patients and tested their ability to block SARS‐CoV‐2‐S‐driven entry; these antibodies efficiently offered at least partial protection against SARS‐CoV‐2.3.1.2The host receptors  contribute to cell entry of SARS‐CoV‐2 through binding with different domains of Spike protein.Bemcentinib was reported to be a highly selective and potent AXL inhibitor with antiviral activity and was specifically show to block entry of SARS‐CoV‐2 into pulmonary and bronchial epithelial cells.3.1.3SARS‐CoV‐2 was reported to enter cells via binding to host cell receptors, followed by priming by TMPRSS2, Furin and CatL. N‐0385, a peptidomimetic tetrapeptide compound identified in a small library of drugs screened against influenza A virus, was reported to be a TMPRSS2 inhibitor, which impairs the proteolytic activation of Spike protein of different SARS‐CoV‐2 subvariant viruses of concern and blocks viral‐cell membrane fusion and entry.The subtilisin‐like proprotein convertase, Furin, is another attractive target and its inhibitors have shown activity against multiple furin‐dependent pathogens by twofold, including Ebola virus and bird flu virus (A H5N1), via restraining viral entry and enhancing the immune response for viral clearance.3.1.4The in silico drug repurposing strategy has also been used for screening of RdRp inhibitors screening. Vancomycin were recently identified as drugs targeting RdRp and blocking virus replication recently.Andrographis paniculate, inhibited infection by various viruses including HIVpatchouli, has biological effects including antiviral, immunomodulatory, and antitumor.Screening studies involving traditional Chinese medicine compounds identified theaflavin as a potential SARS‐CoV‐2 RdRp inhibitor. Similar compound structures were identified through a molecular docking study as able to target RdRp of SARS‐CoV‐2, SARS‐CoV, and MERS‐CoV.3.1.5Salvia miltiorrhiza (Danshen), including tanshinone IIA, tanshinone IIB, methyl tanshinonate, cryptotanshinone, tanshinone I, dihydrotanshinone I, and rosmariquinone, strongly inhibited PLpro.O‐methylbavachalcone, psoralidin,Previous research has demonstrated that two SARS‐CoV‐2 proteases, Mpro and PLpro, are relatively stable compared with the Spike protein.S. baicalensis and its ingredients, baicalein, were found to inhibit the replication of SARS‐CoV‐2 via targeting 3CLpro.A novel in‐cell protease assay (ICP) combined with docking studies were used with a library of 64 repurposed drugs and led to identification of several SARS‐CoV‐2 Mpro inhibitors, including MG‐101, lycorine HCl, nelfinavir mesylate, lomibuvir, and BMS‐707035.PLpro inhibiters are able to block viral replication by shutting down the active site of PLpro, and they are believed to decrease the activity of PLpro by binding at an allosteric site.3.2Host kinases are essential for all stages of the virus life cycle and are linked to the transmission of SARS‐CoV‐2 and symptoms related to SARS‐CoV‐2 infection, including cytokine synthesis, inflammation, and fibrosis. These potential effects of kinases make them attractive targets in the battle against infection or pandemic.xs3.2.1SRC family kinases have been reported to be crucial for the viral life cycle in MERS‐CoV and West Nile virus and may be potential targets for SARS‐CoV‐2.As the NAK family is regarded as an essential mediator of viral infection, assembly and egress for SARS‐CoV‐2, NAK could be an appropriate candidate for antiviral strategies against SARS‐CoV‐2 infection. Therefore, numerous drugs that have been authorized by the US FDA3.2.2EGFR overexpression not only influences cell proliferation but also affects inflammation, immune thrombosis, and fibrosis, which eventually leads to serious and potentially deadly disease in patients diagnosed with COVID‐19. Gefitinib and erlotinib, the EGFR‐targeting inhibitors, have been verified to be active against HCMV and HCV both in vitro and in vivo.3.2.3Inhibitors of the PI3K/Akt/mTOR pathway can exert antiviral effects. For example, the mTOR inhibitors, everolimus and rapamycin, have been shown to suppress HIV or MERS infection in preclinical settings.292 Further, VPS34‐IN1, an inhibitor of the class III PI3K Vps34, significantly suppressed SARS‐CoV‐2 replication in vitro.Pictilisib, an effective anti‐PI3K inhibitor, was shown to reduce viral replication in cells with an IC50 of 2.58 μΜ.3.2.4CDKs are involved in cell proliferation and play a role in viral infectivity. Up to now, numerous inhibitors targeting CDKs have been developed or approved for cancer treatment. Moreover, many have been proposed to be repurposed for combating SARS‐CoV‐2. Silmitasertib, a CDK inhibitor in clinical trials for treatment of COVID‐19, displayed significant antiviral activity with an IC50 of 1.28 M.In a recent study, CIGB‐325 was investigated for its role in coronavirus infection based on targeting CK2.3.2.5Signaling via p38 has recently been proven as one of the key pathways for the replication of SARS‐CoV‐2. p38 MAPK regulates not only viral infection, but also inflammatory responses. Hence, numerous drugs that have been approved are considered appropriate options for the treatment of COVID‐19. Following treatment with SB203580, a p38 inhibitor, the replication of SARS‐CoV‐2 was reduced to a large extent without obvious cellular cytotoxicity.3.2.6Currently, repurposing of inhibitors of JAK/STAT as a treatment for cytokine storm associated with COVID‐19 is under investigation. Ruxolitinib, an orally available JAK inhibitor, has shown significant reduction in the levels of increased cytokine production linked to hyperimmune syndrome.3.2.7Given the remarkable impact of GSK‐3 on physiological processes and vital roles in the onset of clinical symptoms related to viral infections, GSK‐3 is considered a promising target of SARS‐CoV‐2. Indeed, a large number of inhibitors have been repurposed and are under investigation, including lithium, lithium chloride (LiCl), kenpaullone, tideglusib, and thiadiazolidinone. Lithium is a GSK‐3‐targeting inhibitor that was approved for patients diagnosed with bipolar disorder.3.3The SARS‐CoV‐2 virus can cause clinical symptoms ranging from mild, such as fever and cough, to moderate, such as pneumonia and localized inflammation that require hospitalization, to severe symptoms, such as ARDS, cytokine storm, multiorgan failure, and fatality.3.3.1Excessive secretion of IL‐6 leads to tissue damage and impairs NK cell antiviral activity.Monoclonal antibodies blocking IL‐1β, IFN‐γ, TNF‐α, IL‐12/23, IL‐17A, and GM‐CSF have been repurposed for SARS‐CoV‐2‐induced cytokine storm immune disruption. Several drugs targeting IL‐1β signaling have been repurposed for clinical treatment of COVID‐19, including the IL‐1β antagonist, canakinumab , and the IL‐1 receptor antagonist anakinra .Blocking of TNFα is supported by numerous studies as a potential treatment strategy for excessive cytokine release and hyperinflammation associated with COVID‐19. The approved TNFα antibodies, infliximab and adalimumab, were originally indicated for chronic inflammatory diseases and are now considered for COVID‐19 treatment.α, IL‐6, and MCP‐1.It is predicted that the active ingredients of Maxing Ganshi decoction, kaempferol and quercetin, may inhibit the coagulation pathway triggered by IL‐6, as well as reduce the level of TNF‐α and IL‐1β.GM‐CSF has been shown to activate innate and adaptive immune responses, and it improves the ability of the body to fight against viruses. Human recombinant GM‐CSF, including sargramostim and molgramostim, are under consideration for the treatment of COVID‐19. SARS‑CoV‑2 infects epithelial cells and destroys the pulmonary physiological barriers; this leads to imbalanced GM‑CSF regulation and thus elevated G‑CSF levels in the peripheral blood of patients with COVID‑19. The blockade of GMCSF could be a viable treatment strategy for COVID19 to achieve clinical benefit. Notably, at least 10 clinical trials have been initiated using this strategy. GM‐CSF antibodies, such as mavrilimumab and lenzilumab, are indicated for autoimmune diseases and inflammatory diseases, such as RA or giant cell arteritis; these are now under investigation as potential therapies for COVID‐19. There are several clinical studies underway evaluating the effectiveness of mavrilimumab for severe COVID‐19 . Similarly, clinical investigation of lenzilumab for severe COVID‐19 showed significant and rapid clinical improvement, reduction of inflammation, and reduced progression to ARDS . In addition, several GM‐CSF inhibitors, including otilimab, gimsilumab, and TJ003234, are under evaluation in clinical trials for COVID‐19 .Other options include blockade of the transcriptional regulator BRD2, a host protein that controls transcription of IFN response in virus infection. A recent study showed that blocking BRD2 may restrain the cytokine storm response associated with COVID‐19.Blockade of thymosin is reported as an immune enhancer and widely used in the adjuvant treatment of chronic inflammation and autoimmune diseases.3.3.2The PI3K/Akt/mTOR pathway is involved in initiating the inflammatory response and producing cytokines, thus triggering cytokine storms, and is also involved in viral replication.The deregulation of inflammatory responses linked to NF‐κB and p38 MAPK was demonstrated for SARS‐CoV‐1, which leads to serious disease.The JAK/STAT pathway is the downstream of IL‐6 and other cytokines involved in cytokine storm during viral infection.GSK‐3 also incites systemic inflammation, which worsens disease through synthesizing the proinflammatory factors like IL‐6, IL‐1β,IL‐18, IFN‐γ, and TNF‐α.3.3.3Mesenchymal stem cells (MSCs) are an effective immunotherapy for the treatment of several disorders, including graft‐versus‐host disease, inflammatory bowel disease, osteoarthritis, RA, and multiple sclerosis. Recently, much attention has been paid to the use of MSCs for reducing pathological changes in the lungs.Another option for severe COVID‐19, for control of inflammatory cytokines and coagulopathy, is blood purification therapy, which was previously used for various severe refractory disorders, such as fulminant liver failure, transplant rejection and collagen diseases.TPE effectively separates plasma from blood cells and replaces it with fresh frozen plasma. Case reports have been published showing successful TPE treatment for patients with severe COVID‐19.4Pharmaceutical companies globally are focusing on developing medicines against SARS‐CoV‐2. However, the initial investment in new medical research and development has been expensive, the process is lengthy, and clinical trial outcomes are uncertain. Therefore, it is attractive to repurpose currently available drugs that target key proteins important for COVID‐19. Currently, many types of drugs, including antiviral agents, antibiotics, kinase inhibitors, and immunoregulators, are being investigated in clinical trials as monotherapy or as part of combination therapy for the treatment or prevention of COVID‐19 Table .249, 4.1CQ is a Toll receptor and autophagy inhibitor.4.2Azithromycin is an antibiotic that is widely used in the study and treatment of bacterial infections.4.3Lopinavir is an AIDS therapeutic drug that selectively inhibits HIV‐1 protease, inhibits HIV‐1 maturation, and prevents HIV infectivity.4.4Cepharanthine is an extract of Stephania chinensis, a traditional Chinese medicine, which was traditionally used to increase the amount of white blood cells and boost the body's immunity to tumors; it can also be used to treat silicosis and hair loss.4.5Bemcentinib is an efficient and selective AXL inhibitor.4.6Favipiravir is an analog of guanine and an effective and selective inhibitor of RNA polymerase; it is approved in Japan for the alternative treatment of influenza.4.7Molnupiravir is an oral prodrug for the ribonucleoside analog EIDD‐1931. Molnupiravir has exhibited substantial activity against influenza viruses and coronaviruses, and therefore it has been investigated in several clinical trials due to its therapeutic potential as a therapy for COVID‐19 and seasonal treatment.4.8VV116 (JT001), an oral nucleoside analog antiviral drug, that is one of the most focused China‐developed COVID‐19 treatment candidates.4.9Remdesivir, a nucleoside analog with antiviral activity, was originally created as an Ebola treatment by inhibiting RdRp activity, however clinical results were negative.4.10Azfudine is the world's first dual‐targeting inhibitor that targets HIV reverse transcriptase with the accessory protein Vif. This agent has exhibited antiviral activity against HIV, HBV, and HCV and inhibits NRTI‐resistant viral strains, as well as HIV‐1 and HIV‐2.4.11PF‐07321332 is a highly effective, orally active 3CLPRO inhibitor for SARS‐CoV‐2. It is a trypsin‐like protease inhibitor that inhibits sodium channel function in airway epithelial cells.4.12Ensitrelvir is the first orally active, noncovalent, nonpeptide 3CL protease inhibitor developed for SARS‐CoV‐2.4.13Masitinib is a potent, orally available, and selective c‐Kit inhibitor that also inhibits PDGFRα/β, Lyn, Lck, FGFR3, and FAK.4.14Sabizabulin is a highly efficient and orally available α/β tubulin (tubulin) inhibitor, which can destroy the intracellular transport of the virus along microtubules. With strong antiviral activity and a demonstrated anti‐inflammatory effect, this agent was believed to have the potential to alleviate cytokine storm caused by the novel coronavirus.4.15Baricitinib (Olumiant) is a dual JAK1 and JAK2 inhibitor that was first approved for therapy of adults with severe alopecia areata.4.16The IL‐1 receptor antagonist, anakinra (Kineret), was first approved for the treatment of RA in 2001 and is now being used as a therapy for COVID‐19.4.17The IL6R antibody, tocilizumab, previously approved for RA and used in the treatment of cytokine storm caused by chimeric antigen receptor T cell (CART) therapy,5The outbreak caused by SARS‐CoV‐2 threatened the world with increasing infection and massive casualties.There is an urgent need to identify potential pathogenic proteins or pathways that are highly conserved among multiple virus, such as Ebola virus, MERS‐CoV, and more recently, coronaviruses.Cost‐effective and timeline‐reducing drug repurposing approaches could be a viable treatment alternative for COVID‐19 to the more traditional drug development process.There are many promising alternative drugs that are being investigated in clinical trials or that have been approved for treating COVID‐19 patients, either alone or in combination with other treatments Table . Some reWhen repurposing authorized drugs for new therapeutic uses for COVID‐19 patients, the specificity of inhibitors on target proteins must be considered in order to avoid adverse effects/unwanted toxicity, and short‐term therapy could be investigated for mitigation of unwanted side effects as well. Combination therapy is a promising approach that could be employed for higher treatment efficacy. Antiviral drugs are often combined with other antiviral agents having different targets, such as ritonavir‐lopinavir,Global collaborative efforts between researchers and healthcare professionals toward drug discovery and development is continuously needed to prevent future pandemics and to restrict the spread of current problematic contagions. In addition to immunosuppressed individuals who are unable to mount responses even after two vaccine doses,Y. X., H. M., and J. Y. wrote the manuscript and prepared figures and tables. Y. C. helped with figures and tables. J. Y., E. W., Q. L., and J. G. provided valuable scientific feedback. All authors have read and approved the final manuscript.The authors declare no conflict of interest.Not applicable.


In July 2022, two Risso's dolphins were reported stranded in Hrútafjörður , a fjord in northern Iceland. These events represent the first confirmed observations and strandings of Risso's dolphins in Icelandic waters. Given the uniqueness of these events, a decision was made to conduct full necropsies on these individuals. This study reports findings from viral and parasitological investigations, morphological and fitness measurements, as well as stomach and intestine content analysis for each of the Risso's dolphin specimens. The results of the necropsies do not suggest any other cause of death than lack of food and exhaustion. A large plastic fragment in one individual's stomach supports these suggestions. The presence of those specimens in the middle of the subarctic ocean illustrates ongoing changes in spatial distribution expanding northward, impacting not only Risso's dolphins but more generally marine life and biodiversity. In July 2022, two Risso's dolphins were reported stranded in Hrútafjörður , a fjord in northern Iceland. These events represent the first confirmed observations and strandings of Risso's dolphins in Icelandic waters. Given the uniqueness of these events, a decision was made to conduct full necropsies on these individuals. This study reports findings from viral and parasitological investigations, morphological and fitness measurements, as well as stomach and intestine content analysis for each of the Risso's dolphin specimens. The results of the necropsies do not suggest any other cause of death than lack of food and exhaustion. A large plastic fragment in one individual's stomach supports these suggestions. The presence of those specimens in the middle of the subarctic ocean illustrates ongoing changes in spatial distribution expanding northward, impacting not only Risso's dolphins but more generally marine life and biodiversity. Grampus griseus (Cuvier 1812) is widely distributed in tropical and temperate waters of both the north and south hemispheres  was reported stranded in Hrútafjörður , a fjord in northern Iceland  since 1982 (strandings) and 1992 (bycatch) and annually reported to the North Atlantic Marine Mammal Commission (NAMMCO) since 1992. So far, no Risso's dolphin has been reported. These events, therefore, represent the first confirmed observations and strandings of Risso's dolphins in Icelandic waters. Given the uniqueness of these events, a decision was made to transport the animals to MFRI headquarters in Hafnarfjörður, southwest Iceland , based on the system for delphinids  and PCR primers M.whale‐PCR‐F‐b (5′‐GAT CGG TGG CCA ACC CGT AGA AC‐3′) and MW‐PCR‐R  to sequences available in NCBI. Sequences for SS214‐1 and SS214‐2  were identical and both shared 99.33%, 99.00%, and 98.83% sequence similarity to NC_012062, LC630882, and AB018584, respectively.During necropsy, all organs were collected and weighed, whenever possible Table . HoweverClistobothrium sp. . These are putatively identified as Clistobothrium delphini  based on host and site of infection. However, morphological identification and molecular confirmation were not possible due to the poor state of the specimens and the DNA being degraded.A complete parasitological investigation was performed on the blubber and the respiratory tracts. After removal, the entire blubber of the animals was thoroughly searched by making incisions from fascia to skin every 0.5–1.0 cm Figure , resultiA parasite investigation was also conducted on the surface of all organs as well as the stomach wall of both animals and the intestine of S2214‐2, yielding no parasites. Furthermore, no hard structures, that is, cephalopod beaks or fish otoliths, were recovered from the intestine.Viral infections were investigated by use of swab pins  collecting samples from brain, bronchi, and lungs of both animals. They were placed immediately into the 3 mL UTM‐RT transport medium (Coban). Tubes were vortexed, centrifuged, and the supernatants were used directly for RNA extraction (RNeasy (Qiagen)). The RNA was tested in Real‐time RT‐PCR (RT‐qPCR) for detection of influenza A virus (IA). For pan‐influenza A virus, a RT‐qPCR assay targeting the M‐gene was used according to Hoffmann et al. . The samhttps://www.woah.org/en/statement‐on‐avian‐influenza‐and‐mammals/). In this study, all the brain, bronchial and lung swabs tested IA‐negative using three different RT‐qPCR targets .Highly pathogenic avian influenza viruses (HPAIVs) of type H5N1 clade 2.3.4.4b has been spreading widely in wild and domestic birds since 2020. This subtype of influenza A virus has also been detected in several terrestrial and marine mammal species  where cold waters predominate ; formal analysis (lead); investigation (lead); methodology ; resources ; writing – original draft (lead); writing – review and editing . Haseeb S. Randhawa: Formal analysis ; funding acquisition (lead); investigation ; methodology ; resources ; writing – review and editing . Guðjón M. Sigurðsson: Investigation ; writing – review and editing . Sverrir D. Halldórsson: Resources ; writing – review and editing . Þorvaldur Þ. Björnsson: Formal analysis ; investigation ; resources . Vilhjálmur Svansson: Formal analysis ; investigation ; resources ; writing – original draft . Sandra M. Granquist: Writing – review and editing . Karl Gunnarsson: Formal analysis ; writing – review and editing . Filipa I. P. Samarra: Formal analysis ; investigation ; writing – review and editing . Christophe Pampoulie: Conceptualization ; funding acquisition (lead); resources ; writing – review and editing .This study has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 817806 (SUMMER project). HSR received funding through a grant from the Eggerts fund (Eggertssjóður), hosted at the University of Iceland, and a Preparatory grant (Sóknarstyrkir) from the Icelandic Research Fund (Rannís).The authors declare no competing interests.


The evaluation of arteriosclerosis (vascular function) is important when treating heart failure (HF). Vascular dysfunction is associated with anemia through renal function and endothelial nitric oxide synthase. Additionally, blood pressure (BP) variability (BPV) caused by vascular dysfunction is also associated with HF prognosis. However, how anemia and BPV may affect HF prognosis is unclear.Between January 2012 and July 2018, 214 patients with HF were hospitalized. The cardio‐ankle vascular index (CAVI) as an index of arteriosclerosis of these patients was measured. The patients were divided into the elevated and preserved CAVI groups. We investigated the factors related to major adverse cardiovascular events (MACEs) as cardiovascular death or rehospitalization within 1 year after discharge.p = .045 [model 1], HR = 0.802, p = .035 [model 2]; preserved CAVI group: HR = 0.783, p = .049 [model 1], HR = 0.752, p = .023 [model 2], and HR = 0.754, p = .024 [model 3]).In the elevated CAVI group, significant differences in body mass index (BMI), BPV, left ventricular dimension, and hemoglobin levels were observed between patients with and without MACEs. In the preserved CAVI group, significant differences in BMI, diastolic/mean BP, and hemoglobin levels were observed between those with and without MACEs. The multivariate analysis showed an independent association between hemoglobin levels and MACE occurrence in both the elevated and preserved CAVI groups .In both the elevated (A) and preserved (B) cardio‐ankle vascular index (CAVI) groups, patients with low Hb levels had more major adverse cardiovascular events (MACEs) 1 year after discharge of acute decompensated heart failure (grouping according to the median Hb level). The multivariate analysis showed an independent association between hemoglobin levels and MACE occurrence in both the elevated and preserved CAVI groups (C; elevated CAVI group: hazard ratio [HR] = 0.800,  ABIankle–brachial indexADHFacute decompensated heart failureBMIbody mass indexBNPbrain natriuretic peptideBPblood pressureBPVblood pressure variabilityCAVIcardio‐ankle vascular indexCSclinical scenarioCTRcardiothoracic ratioCVcoefficient of variationeGFRestimated glomerular filtration rateESAserythropoiesis‐stimulating agentsHbhemoglobinHDLhigh‐density lipoprotein cholesterolHFheart failureHFpEFheart failure with preserved ejection fractionHFrEFheart failure with reduced ejection fractionIDiron deficiencyLDLlow‐density lipoprotein cholesterolMACEmajor adverse cardiovascular eventsNYHANew York Heart Association classificationPPpulse pressurePWVpulse wave velocityRAS‐Isrenin–angiotensin–aldosterone system inhibitorsSDstandard deviationTGtriglycerideTTEtransthoracic echocardiography1The heart failure (HF) pandemic is an issue that refers to a growing number of patients with HF. By 2030,Impaired vascular function is associated with anemia through renal function and endothelial nitric oxide synthase.However, how anemia and BPV affect HF prognosis is unclear. In this study, we evaluated how anemia and BPV affected the 1‐year prognosis of patients with HF classified according to their vascular function.2This study was approved by the Ethics Committee of Toho University Omori Medical Center . This study was a retrospective observational study conducted at a single center according to the Declaration of Helsinki . The medical records of the patients were accessed between January 2020 and June 2022. After that, the collected data were analyzed for research. We have publicized the implementation of the clinical research on the electronic bulletin board in Toho University Omori Medical Center, and we have posted the details of the study in an opt‐out format on the website of Toho University Omori Medical Center and our department (Department of Cardiovascular Medicine). The subjects for this study were disclosed and provided the opportunity to decline to be further enrolled in the study (opt‐out). Because data were evaluated retrospectively and pseudonymously and were solely obtained for treatment purposes, the requirement of informed consent was waived by the Ethics Committee of the Toho University Omori Medical Center (opt‐out).2.1In this study, we used the cardio‐ankle vascular index (CAVI) to investigate vascular function. We recruited 214 patients with acute decompensated HF (ADHF) hospitalized at our institution between January 2012 and July 2018, who met the inclusion criteria for the study. We diagnosed ADHF using the guidelines of the American Heart Association or the European Society of Cardiology.2.2In this study, the main outcome was the relationship between major adverse cardiovascular events (MACEs) at 1 year, anemia, and BPV. MACE was defined as cardiovascular death or rehospitalization due to ADHF. The variables in patients with MACEs were compared with those in patients without MACEs and between the elevated and preserved CAVI groups. The elevated CAVI group consisted of patients with CAVI ≥ 9.0, and the preserved CAVI group comprised patients with CAVI < 9.0. Furthermore, multivariate analysis was performed to predict the occurrence of MACEs.2.32 (m2). The patients were assessed for clinical scenario classifications (CS) based on systolic BP.We investigated age, sex, weight, height, New York Heart Association classification (NYHA), hospital stay, BP, and heart rate. We also calculated the body mass index (BMI) using the following formula: BMI = weight (kg)/height2.4For physiological and functional examinations, transthoracic echocardiography (TTE) was performed and the CAVI was measured. Two physicians blinded for the study performed TTE. Left ventricular systolic function and left ventricular end‐systolic/end‐diastolic and left atrial dimensions were used to measure heart size. The EF was calculated using either the modified Simpson method  or the Teichholz method .VaSera VS‐1500E  was used to measure the ABI and CAVI after 12 h of fasting in the morning following ADHF improvement.2.5X‐ray obtained on admission to determine the cardiothoracic ratio (CTR). Two blinded physicians calculated the CTR using the maximal cardiac and intrathoracic diameters.We analyzed the laboratory results for C‐reactive protein, liver function , Hb, electrolytes , brain natriuretic peptide (BNP), and renal function . The eGFR was calculated using the Japanese Society of Nephrology criteria, as follows: eGFR = 194 × Cr − 1.094 × age − 0.287 for men and 194 × Cr − 1.094 × age − 0.287 × 0.739 for women.2.6The use of cardioprotective medications, such as β‐blockers, renin–angiotensin–aldosterone system inhibitors (RAS‐Is), and mineralocorticoid receptor antagonists, was evaluated. RAS‐I was defined as angiotensin‐converting‐enzyme inhibitors or angiotensin II type 1a receptor blockers. We investigated the rates of administration of cardioprotective medications at discharge. For β‐blockers and RAS‐Is, we investigated the proportion of patients who received ≥50% of each maximum dose from the package insert information.2.7t‐test to compare the groups. In all cases, differences with p < .05 were considered statistically significant. Excel (Microsoft XP) and EZR, a graphical user interface for R, version 2.13.0 , were used for all statistical analyses and were run on a Windows computer.Data are presented as medians or means ± SDs. We used the Mann–Whitney U test or the unpaired Student's 33.1Supporting Information: Tables 3.2Supporting Information: Tables 3.3p = .003). Moreover, patients with MACE2 had a significantly higher proportion of those with anemia . These findings were similar in the preserved CAVI group . Multivariate analysis showed that Hb was independently associated with the occurrence of MACE in both groups  in which our hospital also participated.4.5The most important study limitation is the number of study subjects. This study was a retrospective, observational, single‐center study. The sample size was small because vascular function was not evaluated in all patients. Besides the CAVI, reactive hyperemia, flow‐mediated vasodilation, peripheral arterial tonometry, and PWV are known vascular function evaluation methods.Additionally, in this study, no patients had autonomic disorder; however, the possibility that underlying diseases and medications affected BPV cannot be denied. Furthermore, the data for this study were extracted from medical charts. Therefore, we could not evaluate frailty associated with HF prognosis because no description of the grip strength or quality of life table/score was provided. Because left ventricular diastolic dysfunction was not evaluated in all patients, and this study was retrospective, the data that could be extracted were limited.4.6To address the aforementioned limitations conducting studies with a large number of subjects is essential. The concomitant use of other arteriosclerosis assessment methods is also useful. We also evaluated short‐term BPV during hospitalization ; however, BPV evaluation after discharge in these subjects may also be useful. Further clinical prospective studies with a larger number of consecutive subjects are required to confirm the results of this study.5Anemia was independently associated with the prognosis of HF with or without arteriosclerosis.Shunsuke Kiuchi contributed to the study concept and the acquisition of the data. All authors reviewed the raw data and contributed to the analysis and interpretation. Shunsuke Kiuchi drafted the manuscript and Shinji Hisatake, Takayuki Kabuki, Shintaro Dobashi, Yoshiki Murakami, and Takanori Ikeda revised it. Finally, all authors approved the final manuscript.T. I. received research funds and lecture fees from Daiichi‐Sankyo, Co., Ltd., Bayer Healthcare, Co., Ltd., and Bristol‐Myers Squibb, Co., Ltd. The remaining author declares no conflict of interest.Supporting information.Click here for additional data file.


The most common type of cancer in the world is lung cancer. Traditional treatments have an important role in cancer therapy. In the present review, the most recent findings on the effects of medicinal plants and their constituents or natural products (NP) in treating lung cancer are discussed. Empirical studies until the end of March 2022 were searched using the appropriate keywords through the databases PubMed, Science Direct and Scopus. The extracts and essential oils tested were all shown to effect lung cancer by several mechanisms including decreased tumour weight and volume, cell viability and modulation of cytokine. Some plant constituents increased expression of apoptotic proteins, the proportion of cells in the G2/M phase and subG0/G1 phase, and Cyt c levels. Also, natural products (NP) activate apoptotic pathways in lung cancer cell including p‐JNK, Akt/mTOR, PI3/ AKT\ and Bax, Bcl2, but suppressed AXL phosphorylation. Plant‐derived substances altered the cell morphology, reduced cell migration and metastasis, oxidative marker production, p‐eIF2α and GRP78, IgG, IgM levels and reduced leukocyte counts, LDH, GGT, 5′NT and carcinoembryonic antigen (CEA). Therefore, medicinal plant extracts and their constituents could have promising therapeutic value for lung cancer, especially if used in combination with ordinary anti‐cancer drugs. We collate findings from in vitro and in vivo studies and clinical trials and provide the proposed molecular and cellular mechanisms of action. The biochemical properties of each plant and its constituents are described before exploring their potential as an alternative and complementary treatment of lung cancer.2In vivo and in vitro reports regarding the effect of NP on lung cancer were explored using the databases PubMed, Science Direct and Scopus until the end of March 2022. Accordingly, keywords including lung cancer, medicinal plants, plant constituents, NP, in vivo, in vitro and clinical studies were used.Several criteria were used to select eligible studies for this review: 1) in vitro, in vivo  and human studies, (2) NP supplementation and their dosage, (3) the effect of NP on lung cancer, (5) English language articles published in well‐known international journals. The reference classification is depicted in Figure  in vitro33.13.1.1Zataria multiflora (Z. multiflora) is a traditional herb belonging to the Lamiaceae family and grows in the southern and central regions of Iran. Application of Z. multiflora extract, and its constituent carvacrol, led to various pharmacological effects including anti‐inflammation, immunomodulation and antioxidation. The plant extract and carvacrol also reduced paraquat (herbicide)‐induced lung injury via activation of PPAR‐γ.Z. multiflora and carvacrol have been reported in several studies that we discuss below.Z. multiflora, the results of two animal studies indicated that, due to phenol components including carvacrol and thymol, reduction of ROS levels in tissue but in doses more than 0.4 mL/kg for 14 days, Z. multiflora reduced the safety but increased toxicity.Z. multiflora extract and carvacrol on lung cancer are summarized in Table Regarding the safety and efficacy of Z. multiflora its dried powder was mixed with 85% methanol for 48 h and filtered and the ethanol was removed by rotary at 40C°.Z. multiflora essential oil was prepared from the air‐dried plants through hydrodistillation for 3 h using an all‐glass Clevenger‐type apparatus. The essential oil was dehydrated over anhydrous sodium sulphate and stored at 4°C.For the preparation of methanolic extract of Z. multiflora methanolic extract down‐regulated c‐MYC levels and up‐regulated p53 in the U266 multiple myeloma cell line.Treatment with Z. multiflora essential oil (500 mg/kg) reduced tumour weight and balanced T helper 1 levels by increasing the secretion of TNF‐α, Interferon‐gamma (IFN‐γ) and IL‐2 and decreasing IL‐4 levels. However, no significant effects on aminotransferase and alanine aminotransferase activity were found.Two doses of carvacrol nanoemulsion  over 4 weeks in an athymic nude mouse model significantly reduced tumour growth and tumour weight by 34.2% and 62.1%, respectively, and increased the expression of p‐JNK, Bax, Bcl2, Cyt C, Cas‐3, Cas‐9 and β‐actin in lung tissue.Z. multiflora extract, and its main constituent carvacrol, reduced lung cancer virality by decreasing tumour weight and volume, increasing the expression of apoptotic proteins, modulating cytokine levels and cancer cell viability, as well as regulating specific pathways and cancer tumour cell numbers. Therefore, Z. multiflora extract and carvacrol are worth testing as a part of contemporary treatment strategies for lung cancer.Overall, treatment with 3.1.2Nigella sativa (N. sativa) seeds for thousands of years across the African and Asian continents. For example, in the south‐west of Asia, this plant has been used both as a food additive and herbal medicine.N. sativa seeds is thymoquinone (TQ).N. sativa and TQ to have anti‐inflammatory, anti‐oxidative and immunomodulatory properties, and are also effective treatments against allergic disorders, lung cancer and tumour morphology.A variety of diseases have been treated with N. sativa extract and TQ.N. sativa and TQ are both potential treatments for lung cancer.Regarding the safety and toxicity of black seeds and TQ, dependent on the type of animal model and administration manner, the results demonstrated that the toxicity effects of oral administration were lower than intraperitoneal injection and administration of more than 2 and 3 g/kg in the mice increased the risk of the organ toxicity of N. sativa were extracted with 95% aqueous methanol for 24 h. The extract was filtered by a Buchner funnel and re‐extracted with 0% methanol for an additional 2 h and methanol was removed with a rotatory evaporator at 40°C.N. sativa volatile oil used in Salim's study was purchased from Kahira Pharm. and Chem. Co., Cairo, Egypt.Cleaned and dried seeds of N. sativa gold nanoparticles (NsEO‐AuNPs) decreased the hydrophobicity index causing significant suppression of S. aureus (78%) and V. harveyi (46%) biofilm formation, which are common infections in patients with lung cancer.N. sativa plant seed extract (NSE) treatment found it caused a significant down‐regulation of cancer cell viability and altered their morphology. Similarly, NSE treatment  on human lung cancer cells significantly reduced their viability.The administration of essential oil N. sativa (0.2 g N. sativa or 5 g honey/day) as supplements in Sprague Dawley rats showed protection against oxidative carcinogenesis induced by methyl nitrosourea in lung, skin and colon tissues.N. sativa volatile oil (1000 or 4000 ppm) for 30 weeks to male Wistar rats reduced the size of some tumours, including in the lungs.The use of honey and N. sativa and its constituent TQ could be promising candidates for treating lung cancer. Their therapeutic actions involve decreasing cancer cell viability and altering their morphology and levels of Bcl2 proteins, inflammatory markers, oxidative stress parameters and NF‐kappa whilst increasing Bax/Bcl2 ratio and levels of apoptosis.The above in vitro and in vivo results indicate that 3.1.3Crocus sativus L (C. sativus) is mainly cultivated in Iran and is a member of the Iridaceae family. Chemical analyses of C. sativus extract indicate that the most critical constituents are carotenoids, crocin, crocetin and the monoterpene aldehydes crocin and safranal.C. sativus and its critical constituents decrease white blood cell (WBC) counts, reduce oxidative stress markers, impact airway responsiveness and also have immunomodulatory effects.C. sativus, its oral administration of 200 and 400 mg/day for 7 days, indicated the changes in some haematological and biochemical parameters but, these changes were in normal ranges which were not important clinically.C. sativus and its constituents on lung cancer and their potential mechanism was also reported in numerous studies  for 2 h in an ultrasonic bath. Then the extract was filtered and concentrated in a vacuum evaporator.C. sativus extract.Treatment with ethanolic saffron extract  reduced cell number and viability of L929 lung cancer cells.Treatment of lung cancer cells with crocin  markedly enhanced the mRNA levels of p53 and Bax and significantly down‐regulated Bcl‐2 mRNA expression.Albino mice with B(a)P‐induced lung cancer were treated with crocetin (50 mg/kg) and cancer cell proliferation was reduced by 68% and 45% in weeks 8 and 18 respectively, and glycoproteins and polyamines were significantly altered.C. sativus, crocin and crocetin down‐regulate mRNA levels of major proteins of apoptosis in lung cancer cells. Therefore, C. sativus, crocin and crocetin could be considered as treatment strategies for lung cancer.The above results suggest that 3.1.4Ocimum basilicum L. (O. basilicum), or basil, is the main part of the oil crop used in traditional medicine that belongs to the Lamiaceae family. It is widely found in regions of central and southeast Asia, including Iran and Pakistan.O. basilicum.O. basilicum and its constituents have been demonstrated by Alkhateeb et al.O. basilicum and its derivatives reduced inflammation and oxidative stress and improved immune function in patients with asthma, COPD, lung cancer and allergy diseases.O. basilicum were shown in the LD50 > 5 mg/kg such as haematocrit, platelets and RBC decreasing and oral toxicity in patients.O. basilicum consumption in food and drug preparations is safe. However, a concentration limit for alkylbenzenes should be considered, and the plant chemotypes with equal or lower levels of these alkylbenzenes should be used.O. basilicum on lung tumours are summarized in Table Safety results demonstrated that acute effects of O. basilicum and its constituent linalool are a natural therapeutic against lung cancer cells and support further research to test the hypothesis.Treatment of A549 cancer cells with linalool (0–2.0 mM) inhibited cell proliferation and migration but increased the G0/G1 cell cycle arrest. Linalool treatment also sensitized cancer cells and anti‐metastatic markers were recorded in the treated A549 cells.3.1.5Ferula are perennial flowering plants belonging to the Apiaceae (Umbelliferae) family. Ferula growth spans the eastern Mediterranean regions all the way to central Asia.F. szowitsiana and its constituents have been reported in several studies (75–82). As well as F. szowitsiana, studies have found F. persica and its derivative coumarin may possess therapeutic properties.The genus F. persica known as food additive until 1.5–2 mg/kg incresed the fibroblast cells in male patients and improved libido but did not report serious or acute side effects.F. persica and coumarin on lung cancer are summarized in Table Administration F. szowitsiana (100 g) was prepared using the Soxhlet‐extracted method with dichloromethane and methanol (1 L of each) and then was dried by evaporator.Total plant extracts were obtained by extraction of dried and milled aerial parts of the plants with 80% methanol (1:10) using the maceration method for 4 days. After every 24 h, the mixture was filtered and a new solvent was added to the plant powder. The combined extracts were concentrated to dryness under vacuum pressure.F. szowitsiana extract (400 μg/mL for 48 and 72 h) altered anti‐apoptosis, pro‐apoptosis and tumour suppressor gene expression, up‐regulated P53, Bax and Cas‐9 and also activated multiple apoptotic pathways and antiproliferation activity.F. persica extract (100 μg/mL) decreased cell viability and cell proliferation in MDBK, A549, HT29, HepG2 and MCF7 cell lines.Treatment of A549 cells with F. szowitsiana extract showed decreased cytotoxicity via SK‐LU‐1, SPC‐A‐1 and 95D tests and were also less viable.Cell proliferation, invasion, metastasis and autophagy were reduced in lung cancer cells treated with terpenoids. The inhibitory effects of terpenoids on cyclins and CDK were shown.F. persica and its main constituent coumarin as a possible treatment for lung cancer via the inhibition of cyclins and CDK, their reducing effects on cancer cell migration and metastasis mediated by cytokines such as IL‐1β, oxidative marker production, cell viability and cytotoxicity warrant further investigation.Based on the above findings, further investigation in 3.1.6Turmeric, also known as Curcuma longa (C. longa), is a part of the Zingiberaceae family found in some regions of Asia, being particularly abundant in India. In addition to its multiple health benefits, C. longa is an important ingredient in recipes.C. longa and curcumin (CUR) including: antioxidant (7), anti‐inflammatory,C. longa and CUR adopt but further investigation is still needed to ascertain how they work.C. longa and curcumin for 3 months, up to 8000 mg/d did not show side effects in patients, thus, it was recommended that using 2500 mg of C. longa was safe in humans.C. longa and CUR on lung cancer.Clinical results indicated that administration of C. longa rhizome powder (100 g) was dissolved in 200 mL n‐hexane and the solution was shaken for 4 h at 45°C. Then, the supernatant was transferred to a tube. This step was performed three times. Then, the residue of n‐hexane extraction was dissolved in 200 mL dichloromethane instead of n‐hexane and the same steps were repeated. The debris of extraction with dichloromethane was dissolved in 200 mL methanol and in the same way, supernatant was collected. Finally, the solvents of all three phases were dried by rotatory‐evaporator and the remaining powders were stored at—20°C until used.C. longa at concentrations of 0.114, 0.142, 0.171 and 0.199 mg/mL inhibited telomerase in A549 lung cancer cells dose‐dependently.N‐hexane extract of CUR  applied to lung cancer stem cells for 7 days acted as an interventional agent by inhibiting both the Wnt/ß‐catenin and the Sonic Hedgehog pathways.Both pure CUR and nanoencapsulated CUR (CUR‐Fe3O4)  reduced proliferation and hTERT gene expression in lung cancer cells but CUR‐Fe3O4 was most effective.As a result of increasing FOXA2 expression and modulating STAT3 signalling pathways, CUR treatment  inhibited human NCI‐H292 cell growth.Gefitinib is a medication for cancer that inhibits EGFR in target cells. In primary NSCLC cell lines that are gefitinib‐resistant (H157 and H1294), CUR reinstated the anti‐cancer effects of gefitinib.In vitro studies have shown that CUR (10 μ M for 4 days) induces the maturation of lung cancer patient‐isolated regulatory cells (Treg) to T helper (Th)‐1 cells by inhibiting DNA transcription of forkhead protein‐3 (Foxp3) and increasing expression of IFN‐γ. Treatment with CUR in lung cancer patients led to a significant increase in peripheral Tregs compared to healthy subjects.A study was performed using CUR dry powders and liposomal (LCDs) against human lung cancer A549 cells and normal human bronchial epithelial BEAS‐2B cells. CUR and LCDs reduced TNF‐α levels in bronchoalveolar lavage fluid) BALF,  and Cas‐3 levels in lung tissue and expression of VEGF and B‐cell lymphoma 2 (BCL‐2). However, CUR powder showed a much stronger anti‐cancer effect than LCDs.In an animal model of lung cancer, the anti‐carcinogenic effect of CUR  was shown by reduced tumour volume and weight, down‐regulated Notch and HIF1 mRNA expression and inhibited VEGF and NFB.C. longa and CUR have been found to suppress cancer cell proliferation and induce apoptosis of lung cancer cells. Additionally, CUR altered the expression of EGFR, microRNAs and autophagy in cancer stem cells. It is believed that CUR influences the expression of different genes in the cancer cells themselves, such as NF‐kB, STAT‐3 and AP‐1, as well as protein kinases, including MAPK and enzymes such as COX and LOX. Thus, CUR makes for a promising therapeutic target in treating lung cancer.In both in vitro and in vivo studies, 3.1.7Achillea millefolium (A. millefolium), also known as yarrow, is a member of the Asteraceae family and found across Europe, Asia, North Africa and North America.A. millefoliumi on pain and estrogenical wounds were reported and chronic administration (ED50 = 32 mg/kg، p.o) increased above the affects in rats for 90 days but it did not show any serious side effect or toxicity.A. millefolium extracts are safe in the concentrations used in cosmetics.A. millefolium and its constituents, and the findings of A. millefolium effects on lung cancer are summarized in Table The anti‐inflammation and antioxidant and improvement effects of The lyophilized powder (1 g) of the plant was extracted with 40 mL of methanol by stirring  for 1 h and filtered through filter paper. The extract was evaporated at 40°C in rotary to dryness. The ethanolic extract was prepared using the dry fruiting bodies (1 g) with 30 mL of 90% ethanol by stirring for 48 h at 70°C. The extract was filtered and centrifuged to get a clear liquid and evaporated at 40°C.A. millefolium extract on human lung cancer cells (NCI‐H292) increased the level of apoptosis, up‐regulated p53 protein and Bax, activated Cas‐3 protein expression and increased activity of the ER stress pathway, GRP78, Cas‐12 and Cas‐8.A. millefolium extract (75 and 100 μg/mL) altered the cycle profiles, increased apoptosis and increased p53 and p21 expression in HCT‐15 and NCI‐H460 cells.A. millefolium and its constituent kaempferol are broad and lead to cancer cell immobility and death. Compared to the other plant species discussed, A. millefolium has also been reported to disrupt the cytoskeleton of lung cancer cells.Administration of two doses of 3.1.8Portulaca oleracea (P. oleracea) belongs to the Portulacaceae family and grows in Iran, India, Japan, China and southern Europe.P. oleracea with potential anti‐cancer, antioxidant and anti‐inflammatory properties.P. oleracea and genistein treatment reduced inflammation in lung tissue, reduced oxidative stress and improved the Th1/Th2 balance, among other immunological indices.P. oleracea did not show cytotoxic effects in in vitro studies and the IC50 value of more than 10 μg/mL but moderate toxic effects were shown in LD50 value of 1853 mg/kg.P. oleracea poses minimal dangers in humans.P. oleracea, genistein and luteolin on lung cancer cells, which are discussed below and summarized in Table Results were reported that administration P. oleracea seeds was extracted by continuous extraction in Soxhlet apparatus for 12 h using petroleum ether (60–80°C boiling range) as a solvent. Then the solvent was evaporated and kept at −4°C.The oil from dried and grounded P. oleracea treatment (10–1000 ng/mL m for 24 h), a dose‐dependent reduction in cell viability and changes in cell morphology were recorded. In addition, the lung adenocarcinoma cell line (A549) showed decreased proliferation and a higher apoptotic rate compared to controls.Following treatment of HepG2 and A‐549 cells with Considering mRNA and protein levels, glutein therapy increased Bax but decreased Bcl‐2 (anti‐apoptotic factor) in A549 cells.P. oleracea cytotoxic effects on human lung (K562 and A549) and breast cancer (MCF‐7 and MDA‐MB‐435) cells were examined using four alkaloids isolated from air‐dried aerial parts. The alkaloids isolated from P. oleracea showed moderate cytotoxic activity against A549 cells and only weak cytotoxic activity against K562 cells.The treatment resulted in inhibited tumour growth by activating miR‐128 in the tumour cells. Genestein  also suppressed cell proliferation and reduced MMP‐2 expression in human NSCLC cells (A549 cell line) in a dose‐dependent manner.3.1.9Allium cepa L. (A. cepa), or onion, belongs to the Liliaceae family and includes over 250 genera and 3700 species.Allium sativum) is a member of the onion (Amaryllidaceae) family and is classified in the same genus to which onion, leek, chive and shallot belong.A. cepa in humans. Several studies have found A. cepa and CUR works against lung cancer cells and the potential mechanisms are explored below and summarized in Table To our knowledge, there is no published data regarding the safety of Onion bulbs (100 g) was peeled, washed, cut into pieces and crushed and percolated in 500 mL of distilled water for 3 days with intermittent shaking. Using Whattman no.1 filter paper the extract was filtered to get fine.NCI‐H209 lung cancer cells treated with QT (5 μM) glucuronides are less likely to survive but they exhibit a higher percentage of cells in the G2/M phase, subG0/G1 phase and in the G2/M phase over time.A QT‐containing diet is also associated with poorer miRNA expression profiles of the tumour suppressor let‐7 family in lung cancer tissue samples from 264 cases (144 adenocarcinomas and 120 squamous cell carcinomas).A. cepa extract (10 g/L) showed an antiproliferative effect and mitotic indices appeared to be reduced in association with concentrations of the extracts.A. cepa oil (10 mg/kg for 21 days) was shown in rats that had been exposed to nicotine, with higher levels of catalase (CAT) and superoxide dismutase (SOD) noted.A. cepa and its main constituent QT reported in the above studies indicate that A. cepa and QT could inhibit adenocarcinomas parameters by modulating the expression of B‐cell lymphoma, Bax mRNA, Bcl‐2 mRNA, cell viability and DNA synthesis in lung cancer cells.The anti‐cancer effects of 3.1.10Brassica juncea (B. juncea), or mustard leaves, is a cruciferous vegetable consumed in different Asian and African countries.B. juncea has also demonstrated cytotoxic effects against cancer cells from different organs, including the colon, stomach, lungs and breast.F. suspensa extract did not show hepatotoxicity, hemolytic activity or other side effects indicating its safety when used at the studies doses.Adminstration of B. juncea powder (20 g) was dissolved in 100 mL of 100% methanol and kept in a rectangular double‐walled water bath at 50°C for 4 h. Then the excerpt was filtered with filter paper (diameter of 125 mm) and the filtrate was kept at 50°C until it turned into a semisolid form.Dried A. deliciosa and B. juncea extracts increased antioxidant and antiproliferation activity markers and apoptosis in human lung carcinoma cells.DPPH assay analysis found that a combination of In vivo results showed that treatment with sinapic acid  improved lung and body weight, reduced levels of IgG, IgM and leukocyte counts, reduced the function of neutrophils, lipid peroxidation, pro‐inflammatory cytokines, AHH, LDH, GGT, 5′NT and CEA and elevated the phagocytic index, activity index and activity of antioxidant enzymes.The above in vitro and in vivo results indicate that mustard and its constituents could be effective in lung cancer treatment via increasing antioxidant activities and antiproliferation activity markers, apoptosis and improving levels of immunoglobulins, Cas, HMGB1, LDH and pro‐inflammatory cytokines in lung cancer models.3.1.11Aloe Vera (A. vera) is used to treat wounds in traditional Chinese medicine but is also widely used as a food, a remedy for constipation, wound healing and anti‐cancer purposes in Egypt, Greece and China. These medicinal properties have also been tested in pharmacological studies.A. vera and its derivatives on lung cancer and the findings are discussed below and summarized in Table Regarding the safety of the plant, administration of tree doses , did not show any toxicity and mortality.Aloe emodin  to lung cancer (H460) cells increased apoptosis, necrosis and cell death, increased MAP kinase membrane activation of a mitochondrial permeability transition pore, changed Cyt c protein expression and mediated localization of F‐actin.A. emodin  stimulated autophagy through activation of MAPK signalling, inhibition of the Akt/mTOR pathways, reduced ROS levels and mediated autophagy.A. emodin on CH27 and H460 cells found apoptosis was induced via nuclear morphological changes and DNA fragmentation, cystolic Cyt c fractions were enhanced, Cas‐3 was activated and protein kinase C (PKC) expression was increased.A. emodin (40 μM) treatment of CH27 cells also triggered apoptosis by DNA fragmentation and enhanced expression of Bcl‐2 family proteins such as Bcl‐XL, Bag‐1 and Bak which increased Cyt c in the cytosolic fraction. A. emodin administration (20 μM for 2 h) to H460 cells also stimulated protein kinase Cδ (PKCδ) expression and cell death and decreased expression of cytoskeleton‐related proteins, including sarcoma (RAS), RAS homologue gene family member A (RHO), p38, heat shock protein 27 (HSP27), focal adhesion kinase (FAK), α‐actinin and tubulin.A. emodin (40 μM) increased the amount of proform and fragments of nucleophosmin, inducing apoptosis. In a more recent study, apoptosis‐inducing proteins such as cAMP‐dependent protein kinase, protein kinase C, Bcl‐2, Cas‐3 and p38 were also measured in carcinoma H460 cells following treatment with A. emodin nanoparticles (50 μM) for 16 h.A. emodin nanoparticles cleaved Cas‐3, Poly (ADP‐ribose) polymerase (PARP), Cas‐8 and Cas‐9 and simultaneously activated MAPKs and inhibited PI3K/AKT, leading to marked inhibition of cancer cell proliferation, induced cell cycle arrest and apoptosis.Administration of A. vera and A. emodin showed anti‐carcinoma effects on lung cancer cells. Therefore, A. vera and A. emodin could be effective in lung cancer therapy by inhibiting cell proliferation, cytoskeleton activation, stimulated cell apoptosis as well as Cas‐3 and PKC activation, MAPK signalling, inhibition of ROS production, Akt/mTOR and PI3K/AKT pathways.Based on the above studies, 3.2In the present article, the effects of the most effective 11 medicinal plants and their constituents against lung cancer were reviewed. The anti‐cancer effects of the above medicinal plants and their derivatives on lung cancer were mediated through different mechanisms of action including inhibition or abnormal cell growth and proliferation, cancer cell apoptosis and death, oxidative stress and inhibition of migration and or metastasis.3.2.1A. vera, C. longa, C. sativus, B. juncea, A. cepa, P. oleracea, Z. multiflora, N. sativa and their constituents on lung cancer cell proliferation.A. vera, C.longa, F. szowitsiana, P. oleracea and Z. multiflora all demonstrated an ability to block or disrupt tumour growth in lung cancer models and cell lines.In lung cancer, increasing cell proliferation and viability of cancer cells demonstrates the advancement of the disease. Therefore, the effect of natural products on lung cancer cell proliferation and viability is an indicator of their therapeutic effects. The in vitro and in vivo studies demonstrated the inhibitory effects of 3.2.2O. basilicum, P. oleracea, A. vera, C. longa, A. cepa, C. sativus, N. sativa, Z. multiflora and their constituents increased the level of apoptosis in lung cancer models or cell lines.Increased apoptosis reduced rates of lung cancer cell proliferation, growth and prevented metastasis, making it a powerful effect against lung cancer. Several studies reported that the natural products: 3.2.3Magnolia officinalis, was found to inhibit migration and invasion in H1299 lung cancer cells by disrupting the expression of MMP‐9 and the Hsp90/MMP‐9 interactions mediated by HDAC6. Honokiol promoted the degradation of MMP‐9 through the ubiquitin‐proteasome pathway, rather than inhibiting its transcription. HDAC6, a deacetylase, regulates the stability of Hsp90, which is involved in the activation of MMP‐2/9. Honokiol inhibited the expression of acetyl‐α‐tubulin, a specific substrate of HDAC6, and further experiments confirmed the regulation of MMP‐9 by HDAC6.A. millefolium, C. longa, Ferula spp., N. sativa and their constituents reduced lung cancer cell migrationThe extracellular matrix (ECM) is a crucial component of the tumour microenvironment (TME) and is present in both interstitial and epithelial vessels. It plays a dual role in cancer progression, as it facilitates interactions between cancer cells and stromal cells, promoting carcinogenesis, while also acting as a barrier against tumour metastasis.3.2.4Studies investigating various types of cancer have revealed some of the molecular events behind cancer cell proliferation, viability, migration and metastasis. For example, enhanced tumour growth correlated with increased AMPK and fatty acid oxidation in ovarian cancer cells, linked to dysregulation of mTORC1 expression in renal cell carcinoma and has been connected to the hypoxia and oncogenic HRAS or KRAS pathways in glioblastoma and bladder cancer.Hence, p53‐deficient KRasG12D NSCLC had dysfunctional mitochondria, lipid accumulation and defects in fatty acid oxidation, resulting in reduced tumour growth.In microglial, bladder cancer and HepG2 cells, cell proliferation, migration and survival could be enhanced by up‐regulation of the Gadd45 family member Gadd45β/Myd118, which associates with MKK7/JNKK2, p38 expression, transforming growth factor‐β and TGF‐β via the JAK/STAT pathway, ultimately activating toll‐like receptors and interferon‐γin.Increasing accumulation and expression of angiogenesis factors such as VPF and VGEF enhanced metastasis and cell growth in tumour cells. Apoxemia and realizing ROS also triggered angiogenesis factors in human glioma cells.N. sativa, A. emodin, F. Szowitsiana and A. millefolium extracts as well as some derivatives of medicinal plants such as CUR, TQ, carvacrol, genistein, crocin work by increasing apoptosis and authophagy, reducing cell viability or proliferation via RTK and reducing cytotoxicity via inhibition of ROS release and expression.C. longa, A. millefolium, C. sativus, szowitsiana and CURwere also found to Block the Wnt/β‐catenin and Sonic Hedgehog pathways, reduce metastasis and migration of lung cancer cells via inhibition of NF‐κB and AP‐1, MMp2, JAK/STAT3 pathways, increase FOXA2 expression via regulation of STAT3 signalling pathways, enhance GCL expression via activation of Nrf2, LC3‐II, p62 expression rand decrease cancer cell cytotoxicity via inhibition of ROS and inflammatory markers.The cancer suppression effects of 3.2.5Despite the availability of numerous conventional anti‐cancer drugs with diverse mechanisms of action, the majority of them ultimately induce cell death through necrosis, apoptosis or autophagy by stimulating genotoxic stress.Given these limitations, natural compounds have emerged as a promising source of new molecules for chemosensitization due to their unique structures and mechanisms of action. Many plant‐derived molecules have been found to target multiple pathways involved in cancer and are consumed as food or used as traditional remedies. Natural products have played a significant role in the development of small molecules approved for cancer treatment. For instance, between the 1940s and the end of 2014, 75% of the small molecules approved for cancer treatment were other than synthetic, with 49% being natural products or directly derived from it. Therefore, scientists are currently exploring new molecules, such as natural compounds, to address the important problem of MDR in cancer.Natural compounds have emerged as a promising source of new molecules for chemosensitization in cancer therapy due to their unique structures and mechanisms of action. They can be used as chemotherapeutic agents, chemopreventive agents and chemosensitizing agents to improve the effectiveness of conventional chemotherapy.4This review article presented the potential therapeutic effects of medicinal plants and their constituents on lung cancer based on in vivo and in vitro findings. Medicinal plants and their constituents increase the anti‐cancer effects of many chemotherapeutic agents and radiotherapy, as well as reverse the effects of chemotherapeutic drug resistance, which is noteworthy since the emergence of chemotherapeutic drug resistance will eventually compromise the treatment of cancer.Z. multiflora extract and its main constituent carvacrol, reduce lung cancer virality, increases the expression of apoptotic proteins, modulates cytokine levels, cancer cell viability and regulate specific pathways. The effect of C. sativus, crocin and crocetin on down‐regulation of mRNA levels of major proteins of apoptosis in lung cancer cells was also reported. F. persica and its main constituent coumarin are shown as a possible treatment for lung cancer via the inhibition of cyclins and CDK, their reducing effects on cancer cell migration and metastasis mediated by cytokines such as IL‐1β, oxidative marker production, cell viability and cytotoxicity.The reviewed papers showed that the extract of C. longa and CUR suppress cancer cell proliferation and induce apoptosis of lung cancer cells. CUR changed the expression of EGFR, microRNAs and autophagy in cancer stem cells and influences the expression of different genes in the cancer cells, such as NF‐kB, STAT‐3 and AP‐1, as well as protein kinases, including MAPK and enzymes such as COX and LOX. The anti‐cancer mechanisms of A. millefolium and its constituent, kaempferol by change in cancer cell immobility and death as well as disruption the cytoskeleton of lung cancer cells were shown. P. oleracea and its constituent such genestein reduce cell viability, cell proliferation, Bcl‐2 level and MMP‐2 expression but increase apoptotic, cytotoxicity, Bax expression, miR‐128 activation and p21 protein level, inhibit NSCLC cells ERK1/2 and PI3K/Akt phosphorylation, regulate Cas‐3/9 activity, miRNA27a activity and the expression of the MET protein enhancing p62, activating Cas‐3 and Cas‐8 and increasing TRAIL‐induced tumour cell death by activated autophagy.A. cepa and its main constituent QT are shown by adenocarcinomas parameters inhibition through modulating the expression of B‐cell lymphoma, Bax mRNA, Bcl‐2 mRNA, cell viability and DNA synthesis in lung cancer cells. The effects of B. juncea or mustard and its constituents on lung cancer treatment are shown via increasing antioxidant activities and antiproliferation activity markers, apoptosis and improving levels of immunoglobulins, Cas, HMGB1, LDH and pro‐inflammatory cytokines. Based on the above studies, A. vera and A. emodin showed anti‐carcinoma effects on lung cancer cells. It was shown that A. vera and A. emodin are effective in lung cancer therapy by inhibiting cell proliferation, cytoskeleton activation, stimulated cell apoptosis as well as Cas‐3 and PKC activation, MAPK signalling, inhibition of ROS production, Akt/mTOR and PI3K/AKT pathways.The anti‐cancer effects of Therefore, promising effects of medicinal plants and their constituents on lung cancer based on many experimental findings were indicated. However, it is necessary to pay attention to the pharmacodynamic and pharmacokinetic limitations of each medicinal plant. In addition, further clinical studies of the plants and their constituents on lung cancer are needed to justify their use in clinical practice for the treatment of these diseases.Arghavan Memarzia: Writing – original draft . Saeideh Saadat: Writing – original draft ; writing – review and editing . Fereshteh Asgharzadeh: Writing – original draft ; writing – review and editing . Sepide Behrouz: Writing – original draft . Gert Folkerts: Writing – review and editing . Mohammad Hossein Boskabady: Formal analysis ; methodology ; supervision ; writing – review and editing .Not applicable.The authors declare that they have no competing interests.Not applicable.Not applicable.


Left ventricular and left atrial strain are sensitive and reliable markers for evaluating cardiac function in patients with type 2 diabetes mellitus (T2DM), with interactions between the two parameters. The present study aimed to analyze the correlation between global longitudinal strain (GLS) of the left ventricle and glycated hemoglobin (HbA1c) levels in patients with T2DM.A total of 292 patients clinically diagnosed with T2DM were selected and divided into three groups according to HbA1c level. The strains of the left atrium and left ventricle in the three groups of T2DM patients with different HbA1c levels were compared. Univariate and multivariate  linear regression analyses were performed to assess the relationship between strain indicators and HbA1c levels. Generalized additive models were used to examine the relationship between strain indicators and HbA1c levels.p < .05). Univariate and multivariate linear regression analyses revealed that, as HbA1c levels increased, the absolute value of GLS gradually decreased (p < .001). Curve fitting revealed a positive correlation between HbA1c level and GLS, which was not affected by left atrial function.There were significant differences among the three groups in terms of age, microalbuminuria, total cholesterol, fasting blood glucose, postprandial blood glucose, and HbA1c level, and left atrial conduit longitudinal strain (LAScd) and GLS (Left ventricular GLS was independently correlated with HbA1c level in patients with T2DM and was not affected by left atrial function. Among T2DM patients with preserved LVEF, left ventricular GLS, an essential indicator reflecting subclinical changes in the left ventricle, exhibited a positive correlation with increasing HbA1c levels and was not influenced by left atrial function. Due to its high prevalence and associated disability and mortality rates, it has become a serious global health problem.Conventional echocardiography is a commonly used modality for screening and assessing cardiac structural and functional damage in patients with diabetes; however, LV ejection fraction (LVEF) cannot sensitively reflect changes in LV function. In recent years, the development of noninvasive ultrasound imaging techniques has facilitated the determination of subclinical cardiac function. Global longitudinal strain (GLS) of the left ventricle, determined by speckle tracking, is a useful metric for the early identification of subclinical myocardial contractile dysfunction.22.1Data were selected from a consecutive cohort of 302 patients diagnosed with T2DM, who were hospitalized in the Department of Endocrinology at The First People's Hospital of Changzhou  from January to December 2021. Inclusion criteria were as follows: Diagnosis of T2DM according to the American Diabetes Association standards33.1General patient data, including age, sex, body mass index (BMI), duration of diabetes, systolic blood pressure, diastolic blood pressure, heart rate, and history of hypertension and coronary artery disease, were collected. Biochemical analysis was performed on all subjects using standard laboratory techniques. We collected blood samples from patients on the second morning of admission on an empty stomach. We used a fully automatic biochemical analyzer  to measure FPG, HbA1c, total cholesterol (TC), triglycerides (TG), high‐density lipoprotein (HDL), low‐density lipoprotein (LDL), microalbuminuria, creatinine, urine albumin‐to‐creatinine ratio (UACR), and brain natriuretic peptide (BNP).3.2A color Doppler ultrasound diagnostic device equipped with M5S and 4V probes  were used. The echocardiogram examination was simultaneously completed on the second day of hospitalization. All subjects were positioned in the left lateral decubitus position and encouraged to breathe calmly while electrocardiogram was recorded simultaneously. Simpson's biplane method was used to assess end‐diastolic volume, end‐systolic volume, and LVEF. Standard apical four‐, two‐, and three‐chamber images of the left ventricle, the standard horizontal short‐axis section of the mitral valve, the horizontal short‐axis section of the papillary muscle, and the apical horizontal short‐axis section images were acquired in two‐dimensional (2D) mode. The images of all patients were digitally stored for subsequent analysis. Image acquisition and analysis were completed independently by two attending physicians, and the averaged values were taken. Pulsed‐wave Doppler was used to measure peak velocities of early diastolic (E wave) and late diastolic (A wave) mitral valve flow, and the E/A ratio was calculated. Tissue Doppler imaging was used to measure the early diastolic mitral annulus velocity (e′) and to calculate the E/e′ ratio.3.3Calculation of LV GLS: The AFI component of the EchoPAC 203 version  software package automatically tracked the endocardial and epicardial boundaries of the left ventricle, displaying the 17‐segment 2D strain‐time curve and bull's‐eye plot of the left ventricle. If tracing was poor, the endocardial line was adjusted manually, and the image was reread. If accurate tracking could not be achieved for >2 segments after adjustment, the patient was excluded. The software automatically calculated LV GLS, which was used as a metric to evaluate LV systolic function.Measurement of left atrial volume and strain function: One point was taken at the midpoint of the mitral annulus and another point on the endocardium at the left atrial roof. The system automatically sketched and displayed the left atrial endocardial contour. Local manual adjustments were made so that the depiction fitted the boundary. The software automatically generated a left atrial time‐volume curve, and the analysis calculated left atrial maximum volume (LAVmax), left atrial minimum volume (LAVmin), and left atrial presystolic volume (LAVpre). Meanwhile, LASr, left atrial conduit longitudinal strain (LAScd), and left atrial contraction longitudinal strain (LASct) were calculated.3.4http://www.R-project.org) were used for data analysis. The data were stratified according to statistics and HbA1c tertiles. Continuous variables are expressed as mean ± standard deviation (SD) or median , while categorical variables are expressed as frequency (percentage). The χ2 test , one‐way analysis of variance , and Kruskal–Wallis test (for skewed continuous variables) were used to analyze differences between groups.SPSS version 25 (IBM Corporation) and R version 3.4.3 (p < .10), it was included as a potential confounder in the final model. The generalized additive model (GAM) was used for curve fitting. Differences with p < .05 were considered to be statistically significant.To investigate the association between LV GLS and HbA1c level, three different models were constructed using univariate and multivariate linear regression methods, including unadjusted, partially adjusted, and fully adjusted models. In multivariate regression analysis, if the regression coefficient of HbA1c changed by >10% after introducing a factor in the basic model or excluding a factor in the full model, or if the factor was significantly associated with GLS , 98 patients, the mean age was 59.81 ± 10.06 years, n = 47 for men; Group C (12.3 ± 1.4), 97 patients, the mean age was 57.91 ± 10.26 years, n = 56 for men. The basic clinical characteristics of the three groups are shown in Table p < .05). As HbA1c level gradually increased, the GLS value also gradually increased . There was no statistical significance in conventional echocardiographic , left atrial volume , and left atrial strain  indicators among the three groups .A total of 302 patients with T2DM were included in this study, 3 patients had atrial fibrillation, 5 patients had poor ultrasound image quality, 2 patients were diagnosed as coronary heart disease, and 292 patients were finally included Figure . A total4.2p < .05). Specific data are reported in Table Univariate linear regression analysis was performed using LV GLS as the dependent variable and HbA1c along with other factors as independent variables. Results indicated that patient BMI, microalbuminuria, LVEF, and FBG were potential factors affecting LV longitudinal strain (GLS) . In the HbA1c tertile groups, as HbA1c levels increased, GLS values also gradually increased .The results of univariate and multivariate linear regression analyses examining the relationship between LV GLS and HbA1c (continuous variable and tertile groups) are summarized in Table 4.4df = 1, p < .001, F = 41.533), revealing an approximately linear relationship between the two  significantly altered the association between GLS and HbA1c across the various subgroups Figure .5In this study, among T2DM patients with preserved LVEF, LV GLS, an essential indicator reflecting subclinical changes in the left ventricle, exhibited a positive correlation with increasing HbA1c levels and was not influenced by left atrial function. Research has demonstrated that, in most patients with diabetes and subclinical cardiac abnormalities, these abnormalities can be reversed if detected early.T2DM is a metabolic disease caused by various factors, and is characterized by a low‐level inflammatory state and endothelial dysfunction, which increases the risk for cardiovascular disease(s). T2DM can lead to myocardial dysfunction, initially manifesting as subclinical dysfunction, and gradually developing into DCM and HF. DCM is a specific type of cardiomyopathy resulting from diffuse myocardial fibrosis, myocardial hypertrophy, and diabetic microangiopathy.The effects of hyperglycemia on the heart can manifest early; however, patients may not exhibit overt symptoms. Echocardiographic research involving diabetic populations primarily concentrates on LV structure and function; however, conventional parameters, such as LVEF, fail to accurately represent subtle changes in LV systolic function. Results of our study also revealed no statistical differences in conventional echocardiographic parameters, such as LVEF and E/e′ ratio, among individuals with varying HbA1c levels. Speckle tracking echocardiography is a highly sensitive technique that facilitates early detection of overall alterations in LV function. Decreased circumferential and longitudinal strain rates can be identified merely a few weeks after the onset of diabetes.p ≤ .05). Consequently, when studying the relationship between GLS and HbA1c level, the index LAScd may serve as an important confounding factor. After adjusting for confounding factors in this study, including the LAScd index of left atrial strain, the independent association between LV GLS and HbA1c levels was confirmed. Research by Zairi et al. demonstrated that the decline in LV GLS in children with type 1 diabetes was correlated with increased HbA1c levels.There is a close interaction between left atrial and LV function,There were several limitations to the present study, the first of which was the small sample size, which may not have been representative of the entire T2DM population, thus necessitating validation through larger‐scale studies. Second, the determination of LV GLS depended on the image frame rate, and image quality may have affected the accuracy of speckle tracking.In conclusion, results of our study demonstrated that, for T2DM patients with preserved LVEF, as HbA1c levels rise, LV GLS, a crucial indicator reflecting subclinical changes in the left ventricle, was independently associated with GLS and remained unaffected by left atrial function. For T2DM patients with poor blood glucose control and substantial fluctuations, proactive blood glucose management and early intervention should be used to help delay or even reverse myocardial damage and prevent the worsening of cardiac function.Min Xu designed the study and carried out the study, data collection and analysis. Jinmei Gao wrote the manuscript and Mingxia Gong revised the manuscript. Xiaohong Jiang and Ming Chen designed part of the experiments. Shu Jiang and Zhenni Yang collected the T2DM patients. All authors read and approved the final manuscript.The authors declared no conflict of interest.