In the context of climate change, faba beans are an interesting alternative to animal proteins but are characterised by off-notes and bitterness that decrease consumer acceptability. However, research on pulse bitterness is often limited to soybeans and peas. This study aimed to highlight potential bitter non-volatile compounds in faba beans. First, the bitterness of flours and air-classified fractions (starch and protein) of three faba bean cultivars was evaluated by a trained panel. The fractions from the high-alkaloid cultivars and the protein fractions exhibited higher bitter intensity. Second, an untargeted metabolomic approach using ultra-high-performance liquid chromatography–diode array detector–tandem–high resolution mass spectrometry (UHPLC–DAD–HRMS) was correlated with the bitter perception of the fractions. Third, 42 tentatively identified non-volatile compounds were associated with faba bean bitterness by correlated sensory and metabolomic data. These compounds mainly belonged to different chemical classes such as alkaloids, amino acids, phenolic compounds, organic acids, and terpenoids. This research provided a better understanding of the molecules responsible for bitterness in faba beans and the impact of cultivar and air-classification on the bitter content. The bitter character of these highlighted compounds needs to be confirmed by sensory and/or cellular analyses to identify removal or masking strategies. Vicia faba L. minor) ingredients are increasingly used in the formulation of food products due to agronomic, environmental, nutritional, and functional interests +) and the loss of a hexoside residue (−162). Vicine and convicine are the main alkaloids widely spread in Vicia faba [2)–(4) and (6) had one absorption band between 270 and 274 nm and exhibited two characteristic fragments of vicine in their MS2 spectra: m/z 305.1093 ([vicine + H]+) and 143.0564 m/z; they were tentatively identified as vicine derivatives. Only the derivative of vicine ((4), m/z 387.1521 (negative) and 389.1667 (positive)) has already been identified in faba beans +), was also found under a potassium adduct m/z 213.0747 ([M+2K-H]+) and showed a neutral molecular formula of C6H14N4O2. The fragments m/z 158.0926, 130.0975, 116.0707, 112.0870, and 60.0557 were characteristic of L-arginine [8, 9, and 17), suggesting that they were derived from this amino acid. Only N-formyl-L-arginine (9) showing the same molecular formula and its fragmentation has already been identified in another plant, the black cohosh [m/z 198.0762 associated with the fragments m/z 181.0496, 152.0707, 139.0390, and 135.0441 was related to L-DOPA (12) [13) was observed in its protonated (m/z 360.1286) and stacked (m/z 719.2506) forms. The fragmentation patterns revealed the loss of a hexoside residue  and an ammonia moiety ; these observations were consistent with previous results [11) and (19) revealed the neutral loss of a hexoside compared to the compound (20). However, it was not possible to determine a molecular formula by the isotope-ratio method due to the presence of other signals at the same retention time for the compound (19). L-phenylalanine (16) and L-tryptophan (18) were also tentatively identified, and their fragmentations were in agreement with a previous study [15) exhibited the same fragment m/z 146.0601 as L-tryptophan, suggesting that it was derived from this amino acid. Concerning the compounds (10) and (14), their fragments  were similar to those of N-acetyl-L-tyrosine [m/z 224.0918; −162); which suggested that these compounds were two isomers of N-acetyl-L-tyrosine hexoside. N-acetyl-L-tyrosine was produced in common bean plants during fungal pathogen attacks [Many amino acids and their derivatives were detected in positive mode and positively correlated with faba bean bitterness. The compound (arginine . The L-aOPA (12) . An isomus study . The comtyrosine . Moreove attacks . Finally attacks , which s21) was tentatively identified by comparing the accurate MS1 and MS2 spectra from the literature (obtained on a standard) [22) had two absorption bands at 257 and 293 nm characteristic of phenolic acids [m/z 315.0721 and the fragment m/z 153.0194 should indicate the presence of a protocatechuic acid moiety and the loss of a hexoside residue [23), the band at 282 nm and the fragments from MS2 spectra suggested the presence of methylfukiic acid [Piscidia Erythrina L., belonging to the Fabaceae family [Three phenolic compounds, only detected in the negative mode, were positively correlated with bitterness. p-Hydroxybenzoic acid (tandard) . The comic acids ,34. The iic acid ,35. Thise family , wherease family ,19,20,2124) had two absorption bands at 270 and 340 nm corresponding to the phenolic core and the conjugated system of a flavonoid, respectively [m/z 287.0551 indicated the presence of a kaempferol moiety. Many kaempferol derivatives have already been observed in faba beans  and peas (leaves and protein isolates) [The compound (ectively . Moreovesolates) ,19,20,2125) were consistent with those of hydroxy aspergillic acid, and this compound has already been identified in brown alga [26) exhibited the fragments m/z 190.0499, 172.0394, and 144.0444, which should indicate that it was derived from kynurenic acid, which has been identified in olive fruit [1/MS2 spectra of the compound (27) were characteristic of pantothenic acid hexoside [A total of three organic acids were tentatively characterised. The fragmentation patterns in the positive mode of the compound  was tentatively identified as 8-β-D-glucopyranosyloxy-2,7-dimethyl-2,4-decadiene-1,10-dioic acid by comparing the fragmentation patterns with the faba bean literature [29) was detected in both negative and positive modes and exhibited the same fragments as dihydrophaseic acid 4’-O-β-D-glucopyranoside; dihydrophaseic acid and its derivatives were detected in faba beans [A total of two terpenoids were detected. The compound (terature . Anotherba beans .30) detected at 0.74 min exhibited fragments at m/z 104.1071, 60.0808, and 58.0657, indicating that it was derived from choline [2 spectrum but was not positively correlated with bitterness. Second, the fragments m/z 315.1812, 191.0564, 161.0456, 149.0456, 143.0347, and 131.0349 indicated that the compound (31) should be a geraniol pentoxide hexoside [Two compounds were also tentatively identified, but they did not belong to a specific class. First, the compound  revealed the loss of a hexoside moiety . It was not possible to tentatively identify the compounds (40) and (42) because their fragmentation data were not available in the literature. The compound (40) could be a diterpene glycoside called 19-hydroxycinnzeylanol 19-glucoside, which has already been identified in the leaf of a dicotyledon plant [42), the MS1 spectrum was consistent with those of 4-chloro-oxoindole-acetic acid, which have been detected in faba bean seeds [A total of 11 compounds were not identified among the 45 metabolites positively correlated with bitterness; however, a few comments could be made. The fragmentation patterns of the compound  was positively correlated with bitterness according to the logarithmic model, whereas the majority was highlighted by linear (12/31) or both models (18/31). Unlike the PCA from the negative mode, there were two groups of positively correlated compounds with bitterness, each of which appeared to be dependent on the P1 (bottom right) or P2 fractions (top right). N-acetyl-L-tyrosine hexoside (10 and 14) and L-DOPA hexoside derivative (19) were more characteristic of P2, whereas P1 was more related to the presence of vicine (1) and alkaloid derivatives , L-arginine (7) and a derivative (17), L-tryptophan (15), and L-DOPA (13) and its derivatives .A total of 6 alkaloids, 4 phenolic compounds, 14 amino acids, 3 organic acids, 2 terpenoids, 2 other compounds, and 11 unidentified compounds positively correlated with bitterness were tentatively identified . Then, P2, 3, 4, and 6) also activated this receptor, notably if their β-glucopyranoside moiety was free to bind to the active site of TAS2R16 [16) has been shown to activate TAS2R1 and 8, whereas L-tryptophan (18) only activates TAS2R4 and 39 receptors [15) was a derivative of L-tryptophan and could therefore activate bitter taste receptors. L-tyrosine, also a hydrophobic amino acid, exhibits a bitter taste [10 and 14) was characterised by a bitter taste. L-arginine (7) did not activate TAS2Rs, but this amino acid enhanced the bitter intensity of 6-n-propylthiouracil (PROP) and caffeine [21), protocatechuic acid hexose (22), kaempferol derivative (24), and kynurenic acid derivative (26), but the bitter characteristics of the molecules from which they were derived have been determined. p-Hydroxybenzoic acid and protocatechuic acid were perceived as slightly strong bitter and moderately bitter, respectively, at a concentration of 2 g/L in water [Among the alkaloids, vicine (1) is known to activate TAS2R16 and should be partly responsible for faba bean bitterness . This su TAS2R16 . Concerneceptors ,52. Theser taste , which scaffeine . This suin water . TAS2R14in water . The bitin water . In addiThese results were consistent with our previous research focused on the role of saponins (DDMP soyasaponin and soyasaponin βb) and alkaloids (vicine and convicine) in faba bean bitterness. Indeed, alkaloids should be partly responsible for bitterness, whereas the soyasaponin concentration was too low to activate TAS2R receptors . In this10 and 14), but N-acetyl-L-tyrosine was produced in common beans during fungal pathogen attacks [Fusarium circinate, leading to the production of dihydrophaseic acid [Most of the tentatively identified compounds were derived from plant defence metabolism. Alkaloids limit the mollusc repellency of lupin plants . It has  attacks . Phenoli attacks . Concern attacks ,40. In peic acid . There weic acid . In thiseic acid , and theFinally, combining sensory and untargeted metabolomic approaches allowed us to target potential bitter compounds among a high number of metabolites. However, it was possible that some of these compounds were specific to the P1 and P2 fractions without activating the bitter taste receptors. For most compounds, only the chemical class or main moiety from which they were derived was tentatively used to characterise them. It would be interesting to confirm the identification of these compounds by standards and then determine their bitter characteristics by sensory and/or cellular approaches . HoweverIn this study, a combination of sensory and untargeted metabolomic analyses was used to tentatively identify the potential non-volatile compounds responsible for bitterness in air-classified faba bean fractions. Bitterness was more related to high-alkaloid cultivars and P fractions. A total of 42 compounds were positively correlated with bitterness, including 6 alkaloids, 4 phenolic compounds, 14 amino acids, 3 organic acids, 2 terpenoids, and 2 other compounds. However, the tentative identification of 11 compounds remains to be determined. To our knowledge, this work is the first one illustrating the variety of compounds from faba beans that are strong markers of bitterness. It should be interesting to apply our experimental design and this untargeted metabolomic approach to other faba bean cultivars. These results showed that bitter compounds in faba beans were different from those in peas, whose bitterness was more related to flavonoids and saponins. Then, the majority of these compounds were defence metabolites that were generated in the plants or seeds when they were exposed to abiotic or biotic stresses. This suggested that faba beans produced bitter compounds to prevent them from being ingested by pests to ensure their survival. One strategy for reducing the bitterness of faba beans is to select cultivars with low levels of these compounds while ensuring the presence of other defence metabolites to guarantee sensory, agronomic, and economic benefits. It should also be interesting to confirm the identification of the highlighted compounds to verify their ability to activate TAS2Rs by in vitro cellular-based assays or to be sensory detected by panellists. Finally, this approach allowed us to select potential compounds responsible for faba bean bitterness, but it did not consider the interactions between the compounds in the fractions, which could modulate their bitter intensity. However, this approach was relevant for reducing the number of studied compounds and can be applied to other food matrices or to analyse negative perceptions related to volatile compounds in faba beans such as green, rancid, and metallic notes, for example.


Breast cancer (BC) is linked to estrogen receptor alpha (ER-α) positive. Tamoxifen and other estrogen selective modulators have proven to be beneficial in slowing the progression of ER-α BC. However, tamoxifen resistance emerges as a result oflong-term treatment and cancer development. Therefore, it is of interest to document data on the molecular docking analysis of phytochemicals targeting with Estrogen Receptor-alpha. The screening of the phytochemicals from the ZINC database  against ER-α protein was completed. We show that ZINC69481841 and ZINC95486083bind strongly to ER- with binding energies of 10.47 and 11.88 Kcal/mol, respectively, which were significantly greater than the control compound .ZINC69481841 and ZINC95486083 were found to bind with the key residues  of ER-α protein. Data shows that the lead compounds (ZINC69481841 and ZINC95486083) have an acceptable range of ADMET and drug-likeness propertiesfor further consideration in drug discovery. Cancer is defined as a persistent aberrant cell condition or a fatal disease characterized by immortality and uncontrolled cell proliferation. Cancer cells can be invasive, aggressive, and metastatic, spreading to several organs. Breast cancer (BC) is veryheterogeneous in character and disrupts the function of normal mammary epithelial cells. BC is the most prevalent noncutaneous malignancy and the main cause of cancer-related mortality in women globally . It affeThe 3D crystal structure of ER-α (PDB ID: 3ERT) was accessed from the protein data bank (https://www.rcsb.org/structure/3ert). As 3ERT is a homo2-mer structure, one chain was removed and a monomer was used for the docking analysis. The proteinpreparation was done with the help of Discovery Studio's protein preparation tools.Phytochemicals from a commercially available ZINC database   were used  for virtual screening in this study using the PyRx0.8 program. PyRx was employed to prepare the whole ligands before molecular docking to get various binding conformations with the least binding energy (BE).Docking tools like AutoDock and others have made it feasible to quickly screen ligand molecules using posture prediction and ranked list outputs ,17. MoleSwiss ADME (http://www.swissadme.ch/)  and pkCSBC is one of the most common types of cancer in women. Notably, ER-α positivity accounts for 70% of all BC diagnoses, makes it a key therapeutic target. Prospective therapeutic compounds that modulate ER-α are now being explored for the preventionand treatment of a wide range of pathological disorders including the BC . This stZINC69481841 was observed to interact with Met343, Thr347, Leu349, Ala350, Glu353, Trp383, Leu384, Leu387, Met388, Leu391, Arg394, Phe404, Met421, Ile424, Leu428, and Leu525 residues of ER-α ; while Met343, Thr347, Leu346, Leu349,Ala350, Glu353, Trp383, Leu384, Leu387, Met388, Leu391, Arg394, Phe404, Glu419, Met421, Ile424, Leu428, Gly521, and Leu525residues were found to bind with ZINC95486083 . Leu387, Arg394, Glu353 and Thr347 have been determined as active siteresidues of ER-α protein . InteresThe BE values for ZINC69481841 and ZINC95486083 with the ER-α were observed to be -10.47, and -11.88 kcal/mol, respectively, while the inhibition constant were 4.57 and 3.21 µM, respectively (Table 1 - see PDF). Tamoxifen is an antiestrogen. Glu353wMolecular docking has shown to be a useful method and has been utilized in numerous inhibitor discovery investigations to identify potential inhibition mechanisms and to illustrate the nature of molecular interactions between an active molecule and itstarget -26. In dWe describe the molecular interaction of phytochemicals with the estrogen protein.ZINC69481841 and ZINC95486083 show strong binding with the ER protein as well as satisfied adequate ADME criteria for further consideration in drug discovery.


TBC1D12, KERA, and TUBA3D) not previously described as associated with autophagy pathways in cancer. While autophagy-related genes were rarely mutated across human cancers, the expression profiles of these genes allowed the clustering of different cancers into three independent groups. We have also analyzed datasets highlighting the effects of drugs or regulatory RNAs on autophagy. Altogether, these data provide a comprehensive list of targets to further the understanding of autophagy mechanisms in cancer and investigate possible therapeutic targets.In the last decade, there has been a boost in autophagy reports due to its role in cancer progression and its association with tumor resistance to treatment. Despite this, many questions remain to be elucidated and explored among the different tumors. Here, we used omics-based cancer datasets to identify autophagy genes as prognostic markers in cancer. We then combined these findings with independent studies to further characterize the clinical significance of these genes in cancer. Our observations highlight the importance of innovative approaches to analyze tumor heterogeneity, potentially affecting the expression of autophagy-related genes with either pro-tumoral or anti-tumoral functions. In silico analysis allowed for identifying three genes ( Autophagy, a conserved process, plays a vital role in regulating cell metabolism and homeostasis in both physiological and pathological circumstances . By recyMacroautophagy involves the formation of autophagosomes, double-layered membranes that sequester cellular cargo and subsequently fuse with lysosomes for degradation . NutrienChaperone-mediated autophagy is a selective mechanism that relies on specialized molecular chaperones to recognize and deliver specific proteins to the lysosomes for degradation. The chaperone heat shock cognate 70 (Hsc70) plays a crucial role in this process, as it recognizes a specific amino acid sequence motif, called the KFERQ consensus motif, present in target proteins. Upon binding to a protein containing the KFERQ motif, Hsc70 forms a complex with co-chaperones, facilitating the unfolding of the protein and its translocation across the lysosomal membrane. Upon reaching the lysosomal membrane, the complex interacts with a lysosomal receptor called lysosome-associated membrane protein type 2A (LAMP-2A), which aids in the translocation of the target protein into the lysosomal lumen for degradation by lysosomal enzymes .Mitophagy is a cellular process that selectively removes damaged mitochondria through autophagy, thereby preserving mitochondrial fidelity by degrading and replacing damaged mitochondria. When mitochondria are damaged, PTEN-induced putative kinase 1 (PINK1) accumulates on the outer mitochondrial membrane and, after phosphorylation, facilitates binding to substrates ubiquitin and Parkin (PARK2). The ubiquitinated mitochondria are recognized by Sequestosome 1 p62/SQSTM1), a cargo receptor protein, that interacts with microtubule-associated protein 1 light chain 3 (LC3), a component of the autophagosomal membrane [2/SQSTM1,Microautophagy is a non-selective lysosomal degradative process wherein the lysosomal membrane invaginates or protrudes to directly engulf small portions of the cytoplasm or specific organelles .Several cargo-specific autophagy processes have also been reported, including peroxisome removal (pexophagy), endoplasmic reticulum degradation (erphagy/reticulophagy), ribosome degradation (ribophagy), lipid droplet degradation (lipophagy), elimination of invading microbes (xenophagy), clearance of protein aggregates (aggrephagy), and degradation of nuclear material (nucleophagy) .Given the significance of autophagy in cancer, we conducted an analysis of autophagy-related genes in various tumor tissues associated with different types of cancers. The analyzed tumor tissues included bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), testicular germ cell tumors (TGCT), thyroid carcinoma (THCA), uterine corpus endometrial carcinoma (UCEC), colorectal adenocarcinoma (COAD + READ or COADREAD), pan-kidney cohort (KICH + KIRC + KIRP or KIPAN), and stomach and esophageal carcinoma (STAD + ESCA or STES).In this comprehensive review, we compiled and analyzed autophagy-related gene expression data using multiple bioinformatics approaches complemented by reviewing independent literature sources to validate and corroborate our findings. By combining these methodologies, we aimed to enhance our understanding of autophagy pathways and their involvement in the development and progression of cancer.To explore the role of autophagy genes in cancer, we adopted a systematic approach. Initially, we utilized the Molecular Signature Database v2023.1.Hs  in the To evaluate the expression profile of autophagy-related genes in an unbiased method, we performed a differential expression analysis followed by a clusterization by Uniform Manifold Approximation and Projection (UMAP), as shown in For differential expression analysis, we evaluated three approaches: Approach A compares the expression levels between tumor and normal-adjacent samples (only available in the TCGA cohort) using the Mann–Whitney test; Approach B evaluates differentially expressed genes in a large cohort of samples  from the TCGA + GTEx + TARGET cohort using the Mann–Whitney test; and Approach C compares matched samples between normal-adjacent and tumor samples using paired Wilcoxon’s test.These approaches were designed considering that: (i) TCGA is a large patient cohort of tumor samples previously used for different gene-based analyses, even of autophagy-related genes ; (ii) itAfter evaluating common differential genes between these approaches, we continue with the large dataset  using fold change between tumor and normal samples to cluster all tumors depending on autophagy-related factors. n = 16) as a representative value that includes the following tissues: BRCA, COAD, ESCA, GBM, KIRC, KIRP, LGG, LIHC, LUAD, LUSC, OV, PAAD, PRAD, SKCM, STAD, and TGCT. Due to the number of tissues, we ran a principal component analysis (PCA) followed by a UMAP using eight dimensions. Then, we included all autophagy-related genes minimally expressed in the 50% of participant tissues per cluster with a fold change threshold above 1.5 as cluster-associated markers.For this analysis, we included all tissues where the fold changes between tumor and normal samples were estimated using at least 100 participants per group. Then, we considered each tissue , as well as TREM2 (except in LUSC and LUAD), which exhibited underexpression. Specifically, approaches A and C revealed overexpression of RIPK2 and LAMP3 (except in LUSC and LUAD), while Approach B identified overexpression of GAPDH and GRAMD1A. Additionally, TP53 and FRMD5 were found to be overexpressed in Approach B but exhibited underexpression in KIRC, LIHC, PRAD, and TGCT. CDK5R1 showed exclusive overexpression in Approach C. These three approaches allowed us to identify commonly overexpressed genes in the cohort of solid tumors analyzed. Notable genes included A discussion of some of the key findings follows.TOP2A are associated with both sensitivity and resistance to topoII-inhibitor-based chemotherapy [TOP2A (topoisomerase II α) is an enzyme involved in DNA topology rearrangements, and its aberrant expression is linked to various cancer types. It serves as a target for anticancer drugs like Doxorubicin and etoposide, which have been associated with autophagy promotion ,17. Amplotherapy .CENPK (centromere protein K) is a component of the centromeric complex and has been implicated in the progression of ovarian, breast, hepatocellular carcinoma, bladder, and lung adenocarcinoma . AlthougTUBB3 (Tubulin β 3 Class III) is associated with increased chemoresistance and poor prognosis in several cancers, including NSCLC, ovarian cancer, gastric cancer, breast cancer, uterine serous carcinoma, glioblastoma, colorectal cancer, and pancreatic ductal adenocarcinoma. It interacts with LC3, a key player in autophagosome formation .TRIB3 (Tribbles Pseudokinase 3) overexpression inhibits the AKT-mTORC1 axis and autophagy-mediated cancer cell death [TRIB3 upregulation induced by ABTL0812, an anticancer agent under clinical development that induces TRIB3 upregulation and potentiates common chemotherapy regimens in adenocarcinoma and squamous non-small cell lung cancer [ll death . TRIB3 ug cancer .MET is a receptor tyrosine kinase that activates the mTOR signaling pathway, regulating cell proliferation, apoptosis, autophagy, invasion, and tumorigenesis. The ubiquitination and degradation of MET can inhibit the proliferation, migration, and invasion of gastric cancer cells and induce apoptosis .TREM2 is a myeloid receptor expressed by tumor-infiltrating macrophages, commonly found within the tumor microenvironment of human cancers, and inversely correlated with prolonged survival in colorectal carcinoma and triple-negative breast cancer. TREM2 deficiency delays tumor growth in mice . MoreoveP2X7 receptor [To assess the clustering of solid tumors, we utilized the expression levels of autophagy-related genes. To ensure robust observations, we focused on solid tumor types with more than 100 tumor and control samples. Employing this approach, we generated a UMAP plot that revealed three distinct clusters among the sixteen solid tumors analyzed A. The idreceptor . Then, treceptor .ACTL6B, MAPT, PRKAA2, NUPR1, KRBA1, EEF1A2, TUBA3E, and TP53INP1 specifically characterized cluster “0” through their overexpression. Furthermore, we observed that these genes exhibited upregulated levels in tumors belonging to Cluster “0” compared to their normal adjacent tissues. While the limited number of normal-adjacent samples in the TCGA data introduces potential biases and limitations, the majority of the putative markers for Cluster “0” could be validated using the UALCAN tool [Our analysis revealed that the genes CAN tool . A selecPRKAA2 gene exhibited notable overexpression in LIHC, its corresponding protein was significantly downregulated  cohort. In the LIHC dataset, we found a comparable group of normal-adjacent samples, which demonstrated the upregulation of EEF1A2, NUPR1, and MAPT proteins in the tumor group . Howeveregulated . This diegulated , implyinNUPR1 and PRKAA2 genes participate in macroautophagy and its regulation, while MAPT serves as an autophagy regulator, TP53INP1 contributes to autophagosome organization, and ACTL6B and KRBA1 are involved in the autophagy-related network. Additionally, other genes are associated with less-studied forms of autophagy. For example, EEF1A2 is linked to chaperone-mediated autophagy and its regulation, PRKAA2 is involved in lipophagy-related pathways, and TUBA3E is associated with aggrephagy.According to the MSigDB, the NUPR1 in macroautophagy and its impact on the aggressiveness and treatment resistance of specific tumors such as BRCA, LUAD, LUSC, LIHC, and LGG [NUPR1, also known as p8, is a transcriptional regulator that has been shown to reduce apoptosis caused by dihydroartemisinin (DHA), sorafenib, or ionizing radiation (IR) in LIHC tumor cells [NUPR1, in combination with conventional anticancer therapies, has been proven to control tumor growth [NUPR1 using microRNA-637 (hsa-miR-637) as a promising option for this purpose [Previous studies have highlighted the significant role of  and LGG ,41,42,43or cells ,38,39. Hor cells . Additioor cells . Despite purpose .PRKAA2 gene  in gastrointestinal malignancies [PRKAA2 promotes tumor growth in gastrointestinal cancer by suppressing ferroptosis, an autophagy-dependent form of cell death [PRKAA2 activates autophagy-related pathways, leading to treatment resistance, and that its activation can be triggered by the gastrin hormone [PRKAA2 has been shown to downregulate autophagy rates, and metformin has been identified as a potential PRKAA agonist for controlling hepatitis C virus (HCV) replication [PRKAA2 has been associated with a better prognosis [Controversial results have emerged regarding the expression of the gnancies ,47,48,49ll death . On the lication . In gliorognosis . AlthougMAPT gene encodes the microtubule-associated protein tau, which has been extensively studied in Alzheimer’s disease (AD) [MAPT in AD and has demonstrated that overexpression of MAPT/tau inhibits the fusion of autophagosomes with lysosomes, leading to autophagosome accumulation through increased levels of LC3 protein [MAPT and autophagy in cancer remain limited, the high expression levels of Tau protein in glioblastoma, a tumor with enhanced autophagy activity, have raised questions about its possible role in oncogenesis and its implications for cancer therapy [The ase (AD) ,53. Rece protein . Althoug therapy .MAPT gene called MAPT-AS1 has been found to be overexpressed in tumor tissues [In BRCA cohorts, a long non-coding RNA (lncRNA) for the  tissues ,57,58. T tissues .TP53INP1 gene exhibits inconsistent findings across experiments and tumor tissues. Some researchers have identified hsa-miR-106a as an oncomiR that targets TP53INP1 in metastatic lung cancer [TP53INP1 could be crucial in controlling tumor growth through autophagy-dependent cell death. In the case of PRAD, hsa-miR-30a and hsa-miR-205 have been suggested as potential therapeutic options for suppressing TP53INP1 [TP53INP1 is overexpressed as a response to ionizing radiation, which confers resistance [TP53INP1 exhibits a dual function. According to Peuget et al. (2021), oxidative stress induces the expression of TP53INP1 [g cancer , indicatTP53INP1 ,62. Howesistance ,62. TherTP53INP1 . This stTP53INP1 . Thus, ap = 0.004) [In summary, NUPR1, PRKAA2, TP53INP1, ACTL6B, KRBA1, EEF1A2, and MAPT genes are coexpressed with 17 other genes  according to the GeneMania database . These g= 0.004) , allowinSREBF1, OPTN, ACBD5, SESN3, KERA, TUBA3D, FBXW7, TBC1D12, TLR9, and PLK2 show high expression levels in various tumors such as ESCA, PAAD, STAD, COAD, LUAD, LUSC, KIRC, LGG, PRAD, KIRP, LIHC, and BRCA. Furthermore, Clusters “0” and “1” in In addition, after performing a random forest Gini importance analysis, we observed that KERA, TP53INP1, SREBF1, and TUBA3E showed great accuracy (above 75%) and over 75% of Gini contribution . It suggTUBA3D and FBXW7 genes, which are associated with the chaperone-mediated protein folding pathway (R-HSA-390466) according to the Enrichr database [ACBD5, SREBF1, and OPTN genes are also involved in microautophagy pathways, including aggrephagy, mitophagy, and xenophagy.Of particular interest are the ACBD5 gene is interesting in autophagy-related studies as its deregulation can induce their accumulation at protein levels, as shown in Notably, the PLK2, SESN3, TLR9, OPTN, and SREBF1. Independent research has demonstrated that the PLK2 gene controls α-Synuclein aggregation in an autophagy-dependent context [Other genes related to microautophagy processes include  context . Althoug context ,71. An iSESN3 gene, recent studies have identified its role as an autophagy activator in tumor cells by repressing mTORC1 [SESN3 has been observed in LUAD [Regarding the g mTORC1 . Howeverg mTORC1 . Overexp in LUAD  and ESCA in LUAD  models,  in LUAD  or hsa-m in LUAD .TLR9 gene in tumors belonging to Clusters “0” and “1” [TLR9 was found to be upregulated in aggressive versions of LIHC, LUAD, LUSC, and COAD models [TLR9 expression. For example, hsa-miR-30a has been shown to sensitize LIHC cells to a combined therapy of hydroxychloroquine and sorafenib by repressing TLR9 [TLR9 expression in dendritic cells has been suggested as a potential therapeutic strategy, as demonstrated in PAAD cases [About mitophagy, several reports have described the upregulation of the  and “1” ,76,77, i and “1” . ConsistD models ,80,81. Cing TLR9 . On the AD cases . It is iTLR9, OPTN has been extensively studied in the context of mitophagy. PINK1 and PRKN, which are highly studied autophagy-related genes, are also involved in this process. The PHB2 gene stabilizes PINK1 in mitochondria, facilitating the recruitment of Parkin (the product of PRKN), ubiquitin, and optineurin (the product of OPTN) to promote mitophagy [PINK1 and PRKN for initiating mitophagy [OPTN may have tumor suppressor functions by activating suppressor autophagy mediated by HACE1, a tumor suppressor [OPTN has been found to be downregulated in GBM tumor samples, which has been corroborated by independent studies [OPTN expression in GBM cells could help control tumor growth, supporting a suppressive role for this gene, although the underlying mechanism remains unknown.In addition to itophagy ,84,85,86itophagy . Consequppressor ,89,90, oppressor . Importa studies . The samOPTN in the context of mitophagy and the tumor environment, several studies have identified OPTN as a potential therapeutic target. For instance, it has been observed that OPTN induces pro-tumor mitochondrial-related autophagy, reducing the efficacy of combined treatments involving pemetrexed, cisplatin, and MEK inhibitors or anti-PD-L1 in a LUSC model [OPTN leads to apoptosis through chaperone-mediated autophagy [TLR9, understanding the function of OPTN allows us to differentiate its contribution to tumor growth based on its expression in surrounding cells. In LUAD models, higher expression of OPTN in fibroblasts surrounding the tumor contributes to tumor invasiveness [In terms of the application of SC model . In a PAutophagy . Similarsiveness .SREBF1 upregulation has been linked to mTORC1-dependent autophagy, which may be induced by leptins to suppress ferroptosis in BRCA, LIHC, PRAD, and LUAD models [SREBF1 levels were found to be elevated in PAAD tissues, regulated by high glucose concentrations. In PAAD models, the upregulation of SREBF1 helps control autophagy levels [SREBF1 can function as both a protein and a transcription factor. Studies have demonstrated that genes upregulated by the SREBF1 transcription factor can be altered in the presence of cisplatin, inducing treatment resistance in a LUSC model [SREBF1 through FBXW7-mediated regulation to integrate autophagy and lipid metabolism processes, leading to the downregulation of target genes such as acetyl-CoA carboxylase and fatty-acid synthase [D models ,96,97,98y levels . This geSC model . This evsynthase .FBXW7 and SREBF1, it is hypothesized that these tumors exchange autophagy-related processes and large-scale technologies based on their aggressiveness and treatment sensitivity or resistance. However, conducting large-scale high-throughput analyses in mass groups could obscure specific autophagy pathways in certain tumor subtypes or patients. Therefore, the current perspective is to compare global observations with focused research. Nevertheless, the scientific community is moving towards a comprehensive analysis of tumors, considering their heterogeneity and subclonal profile, which will allow us to confirm our current hypotheses about autophagy-related processes in the tumor environment in the future.Considering the combined findings of two genes involved in tumor clusterization, FBXW7 gene has been the focus of numerous studies aiming to characterize its function. This gene is known as a tumor suppressor as it is frequently mutated or suppressed in human tumors [Regarding macroautophagy, the n tumors . Howevern tumors  and downn tumors .FBXW7 has been found to induce the expression of ATG16L1, an important gene involved in LC3 lipidation and autophagosome formation, while not affecting the levels of other autophagy-related genes (ATG) [FBXW7 suppresses mTORC1, thereby activating autophagy pathways [FBXW7 participates in different molecular axes, resulting in different effects on tumor cells. For instance, the GSK3-FBXW7 interaction leads to the ubiquitination and degradation of Rictor, increasing cellular ROS (reactive oxygen species) in an autophagy-activated context [FBXW7 and oncogenes such as SHOC2 or LSD1 can reduce the expression of autophagy-related pathways [FBXW7 and lysosomes [FBXW7 gene can lead to cisplatin-resistant tumors and a poor prognosis. In relation to this, hsa-miR-25 and hsa-miR-223 have been shown to suppress FBXW7 levels, promoting autophagy and treatment resistance in LIHC [FBXW7 levels, but it is important to better understand the specific context in which this strategy would be applicable.Interestingly, es (ATG) . Moreovepathways ,107. FBX context . On the pathways ,107,109.ysosomes . As a re in LIHC  and LUAD in LIHC  models, TBC1D12, KERA, and TUBA3D) that contribute to tumor clustering in groups “0” and “1” have not been previously associated with the tumor-related autophagy process. It is important to emphasize that, in our analysis, the KERA gene was the top gene in Gini relevance and accuracy in tissue pooling of groups between 0 + 1 vs. 2. Studies on mutations in the TBC1D12 gene (TBC1 Domain Family Member 12) have been conducted in urological tumors, suggesting that alterations in its mutational profile could be linked to worse patient survival [KERA (Keratan Sulfate Proteoglycan Keratocan) gene has been found to have lower levels in cisplatin and paclitaxel-resistant OV models [TUBA3D (Tubulin α-3D Chain) gene in BRCA (upregulated) and OV (downregulated) have been validated [TUBA3D was shown to be downregulated in paclitaxel-resistant cells compared to parental cells [Lastly, three genes  that have not been previously associated with tumor-related autophagy.Furthermore, by examining the expression patterns of autophagy-related genes, we were able to classify the 16 solid tumors into 3 distinct clusters. Clusters 0 and 1 exhibited significant involvement of key autophagy-related genes, suggesting shared metabolic pathways and potentially similar therapeutic responses related to autophagy within each tumor type. Interestingly, we also discovered three genes (The comprehensive analysis of autophagy-related clusters in solid tumors, combined with real-world data, holds great potential for identifying therapy targets and conducting further mechanistic studies. However, it is important to acknowledge the limitations of our study. Primarily, our analysis was based on gene expression data, lacking the ability to differentiate between the various cell types within the tumor microenvironment and lacking spatial information about specific molecules. Therefore, additional research and experimental validation are necessary to explore the potential significance of these genes in cancer development and treatment.


The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnostic biomarker, are discussed. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel therapeutic target.Integrins play key roles in mediating cell adhesion and delivering chemical and mechanical signals to the interior of the cell. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Integrin signaling dysregulation can be a major factor in the development of tumors, and it is involved in the processes of the malignant plasticity of the epithelium, the reactivation of metastasis, and resistance to therapeutic interventions. Here, we describe the current understanding of the α6-integrin subunit  in normal and cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnosis biomarker, are discussed. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. In addition, exosomal ITGA6 also implies metastatic organotropism. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel prognostic or diagnostic marker and useful therapeutic target for better clinical outcomes. Over the past decades, our knowledge of integrins has evolved from being understood as simple cell surface adhesion molecules to receptors that have a complex range of intracellular and extracellular functions, such as delivering chemical and mechanical signals to cells. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Dysregulation of integrin signaling is a major factor in the development and progression of many tumors. Many reviews have covered the broader integrin family in molecular and cellular studies and its roles in diseases. Nevertheless, further understanding of the mechanisms specific to an individual subunit of different heterodimers is more useful. Thus, we describe the current understanding of and exploratory investigations on the α6-integrin subunit (CD49f, VLA6; encoded by the gene  Integrins are a family of type I transmembrane glycoproteins ubiquitous in cells and play a key role in cell adhesion to extracellular matrix (ECM) proteins and to neighboring cells . Integriitga6 gene encodes the subunit of alpha integrin (α6) [α6-integrin, also known as ITGA6, CD49f, or VLA-6, is a cell surface protein that mediates cell-to-cell and cell-to-stroma adhesion, which is important for cell proliferation, migration, survival, and differentiation . In epitrin (α6) ,8, whichrin (α6) . ITGA6 drin (α6) ,7,8,11. rin (α6) ; howeverrin (α6) . ITGA6 is expressed from the early stages of development to adulthood and during the development of organs. Its overexpression in retinal pigment epithelia promotes proliferation, which is beneficial for the regeneration of injured tissues . It alsoitga6 mRNA expression in treated cells [In tumor cells, ITGA6 expression and activity improperly change, promoting signaling pathways that govern carcinogenesis, invasion, angiogenesis, metastasis, immune evasion, stemness, and resistance ,6,8,20. ed cells . De Arched cells .itga6, itga3, and itga7 might have a common ancestor [itga6 gene located in chromosome 2 (2q31.1) [itga6 promoter region and enhance its transcription [It has been proposed that ancestor ,28; howe2q31.1) , and itscription ,31,32  and itga6B (ITGA6-B) [itga6 is regulated by epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2), RNA binding motif protein 47 (RBM47), RNA-minding protein muscle blind (MBNL1), RNA-binding protein FOX2 homolog (RBFOX2), and polypyrimidine tract-binding protein 1 (PTBP1) [The pre-mRNA of ITGA6-B) ,31. This (PTBP1) ,31,34 (F (PTBP1) . The C-t (PTBP1)   ,37, whil (PTBP1) .itga6 mRNA, the proteolytic removal of the laminin-binding domain from the tumor cell surface by urokinase-type plasminogen activator  creates α6p [A tumor-specific version with a smaller molecular weight 70 kDa) of ITGA6, α6p, has been identified in various human cancer cell lines. Rather than alternative splicing of precursor 0 kDa of ates α6p . Inhibitates α6p   regulation. It has been reported that miR-143-3p, a tumor suppressor, reduces tumors by targeting and degrading itga6 [itga6 miRNA-mediated degradation [itga6 expression was reported. miR-448 targets and degrades ythdf3 and itga6, which prevents cells from self-renewing [ng itga6 ,42  modification. The m6A methyltransferase complex (“writer”), which consists of methyltransferase-like 3 and 14 (METTL3 and METTL14), catalyzes m6A modifications, which can be reversed by m6A demethylases (“erasers”), such as the fat mass- and obesity-associated protein (FTO) and ALKBH5. The YTHDF2 protein, YT521-B homology (YTH) domain-containing protein, helps m6A-modified transcripts degrade faster, while YTHDF1 and YTHDF3 help m6A-modified target RNA translation more efficiently. Numerous m6A-modified target genes play critical regulatory roles in tumor incidence and progression; in addition, the m6A modification might serve an oncogenic or tumor-suppressive function in diverse cancers .itga6 mRNA expression. Although itga6 mRNA stability and the rate of degradation of the ITGA6 protein remained unaffected, the fraction of itga6 mRNAs undergoing active translation dramatically increased due to raising polysome-bound itga6-mRNA levels [itga6 mRNA by upregulating the m6A modification of itga6 in the 3′UTR region [itga6 mRNA, boosting its protein translation and helping with bladder cancer development and relapse [In bladder cancer cells, the m6A writer METTL3 and the eraser ALKBH5 changed cell adherence by modulating A levels . On the R region , which i relapse ,42.itga6 transcripts in response to FTO overexpression. Accordingly, after FTO overexpression, itga6 mRNA and protein are upregulated in bladder cancer cells [As the first RNA demethylase, the FTO modulates the stability of cellular mRNA by eliminating m6A residues. Many kinds of cancers, including human cervical squamous cell carcinoma tissue and stomach cancer, have high levels of FTO, while bladder cancer has considerably lower expression of FTO levels compared to neighboring normal tissues. The m6A levels increase as the expression of FTO is lowered in a dismal prognosis of bladder cancer patients. The overexpression of FTO in human urinary bladder cancer cell lines (HT-1197 and HT-1376) drastically reduces cell proliferation and invasion capacities while considerably increasing cell apoptosis. Alterations in m6A methylation levels mostly emerge in the 3’UTR of er cells .itga6. Thus, KDM5B promotes the self-renewal of these cells [Histone demethylase lysine-specific demethylase 5B (KDM5B) has been identified as an overexpressed oncogene in a number of malignancies. In the malignant phenotype of hepatocellular carcinoma, KDM5B inhibited miR-448 expression, which, as mentioned earlier, targets and degrades YTHDF3 and se cells  , which subsequently interferes with RTK activation by regular ligands. Integrins, for example, directly bind to integrin-linked kinase (ILK), which forms multiprotein complexes with a number of critical components involved in cytoskeletal dynamics and signaling pathways, causing Akt to be phosphorylated. ILK/Akt is a signaling pathway important for leukemic cell survival ,49,50,51The Src family kinases (SFKs) recruit the focal adhesion kinase (FAK) through integrin beta subunits ,53, whilThe association of integrin α6β4 with laminin substrates results in the activation of Rac1, PKC, PI3K, and ERK signaling pathways, which has been associated with increased carcinogenesis and tumor cell survival . The sigThe ablation of ITGA6 from Ph+ acute lymphocytic leukemia cells results in cell cycle suppression and an increase in the proportion of cells in the G0/G1 and G2/M phases ,59. The itga6 in BCR-ABL (Ph+) acute lymphocytic leukemia cells, the phosphorylation of the docking protein CASL increases, while the phosphorylation of SFK substrates decreases. The phosphorylation of specific tyrosine (Y) in Lyn and Fyn has also been shown in this situation, which decreases their tyrosine kinase activity [After the ablation of the activity . Howeveractivity . In addiactivity . Noteworactivity .In cancers, integrins interact with growth factors, growth factor receptors, cytokines, oncogenes, and enzymes ,56,61,62Depending on the kind of cancer, cancer stem cells are estimated to make up about 0.05–41% of all tumor cells ,40. Selfitga6 with shRNA prevents tumor sphere formation and greatly lowers tumor development. The tumorigenicity of breast cancers decreased after siRNA targeting of itga6 [itga6 [ITGA6 was initially described as a stem cell marker in keratinocyte stem cells with the phenotype CD49f-bright/10G7-dim in 1998 . Since tof itga6 . ITGA6 h6 [itga6 . In addi6 [itga6 . Similar6 [itga6 ,74,75. T6 [itga6 .The self-renewal of human embryonic stem cells (ESCs) and human induced pluripotent stem cells  mainly relies on integrin α6β1 signaling pathways . These pitga6’s promoter region and repressing its transcription [itga6 mRNA, leading to enhanced self-renewal, mammosphere growth, and resistance to paclitaxel treatment [itga6 and enhance its transcription [KLF9 suppresses both glioblastoma cell stemness and tumorigenicity by binding to the cription , whereasreatment . Similarcription   receptor with carcinogenic potential, enhances stemness, drug resistance, and EMT phenotypes in HPV+ head and neck squamous cell carcinoma cells, partially via the PI3K/AKT pathway [Overexpression of  pathway .itga6 and by overexpression of miR-3940-5p, which targets itga6 [EMT is a complicated process that organizes particular changes in cellular phenotype, and it is often accompanied by cell adhesion loss and cell polarity . EMT cauts itga6 . In addits itga6   are closely linked to tumor microenvironments (TMEs) or niches that provide positive crosstalk signals , supportRather than tumor formation at its originating location, tumor cell metastasis is responsible for the majority of cancer-related deaths . The folIntegrins have been found to play a vital role in numerous aspects of tumor metastasis ,89. In pA tumor is a complex biomass encompassing diverse cancer cells, the tumor microenvironment, stroma, and immune cells infiltrating the tumor . When thitga6 promoter, three potential hypoxia response elements (HREs) have been described for the HIF transcription factors [itga6 is reduced at the mRNA and protein levels in HIF-α knockout (KO) of PyMT and MDA-MB-231 cell lines. As a result, selecting cells with high levels of ITGA6 may also result in the selection of cells with a better hypoxic response. HIF signaling also controls the invasion of metastatic breast cancer cells via upregulating ITGA6 [c-Myc and genes involved in the phenotype of cancer stem cells [itga6 expression [Otto Warburg was the first to describe tumor cells’ abnormal metabolic function ,97. Rece factors . Furtherng ITGA6 ,67. Therng ITGA6 . HIF alsem cells ,67,101. The excess synthesis of ECM proteins  characterizes the remodeled matrix ,102. Uprcxcr4, a proangiogenic chemokine receptor, and angpt2 [cxcr4 and angpt2 during endothelium morphogenesis, are known to be activated by laminins and integrins. ITGA6 is necessary for the deposition of laminin-511 and the stability of endothelial tubes once tubes have been formed [The role of ITGA6 in promoting angiogenesis is well documented. For instance, ITGA6 and laminin control the expression of angiogenesis genes such as d angpt2 . Furthern formed . In addin formed .itga6 significantly enhances lymphangiogenesis and lymphatic metastasis in vivo, playing an important role in metastasis to the lymph node and poor prognosis of lung adenocarcinoma patients [cxcr4, itga6) and more robust proangiogenic potential compared to circulating angiogenic cells from the umbilical cord  and healthy individuals [ITGA6 promotes tumor angiogenesis. The overexpression of patients . Despitepatients ,107,108.ividuals . CirculaExtracellular vesicles (EVs), or exosomes, are nano-sized particles that are produced by a variety of cells and have the ability to convey specific payloads such as nucleic acids, microRNAs (miRs), proteins, and lipids; they have been identified as a critical mediator in cell-to-cell communication . Cancer Importantly, certain exosomal integrins found in cancer patients’ plasma samples corresponded with the location of metastases, suggesting that they might potentially predict future metastatic locations at the time of diagnosis ,102,110.ITGA6, mesenchymal stem cell-derived exosomal-miR-3940-5p suppresses colorectal cancer cell invasion and EMT [Through targeting  and EMT ,112,113. and EMT .Because most chemotherapeutic medications are unable to cross the blood-brain barrier (BBB), leukemic cells buried in the CNS are unable to be efficiently removed and hence become the source of recurrent extramedullary leukemia ,115,116.For a long time, it was assumed that leukemia cells entered the CNS through the bloodstream . Howeveritga6 is shown to be downregulated in Nalm-6 cells isolated from CNS compared to bone marrow [Specific integrin binding was predicted to have a role in CSF and CNS invasion and to be highly expressed by acute lymphoblastic leukemia cells in diagnostic bone marrow samples . ITGA6 ee marrow . Accordie marrow . Furthere marrow .MLL rearrangement (KMT2A), hypodiploidy, or TCF3-PBX1 fusion [KMT2A rearrangement. Considering no KMT2A-rearranged cases in Yao et al.’s study of B-acute lymphoblastic leukemia specimens for evaluation of ITGA6 expression, it is possible that molecules other than this integrin are involved in B-acute lymphoblastic leukemia with KMT2A rearrangement infiltrating the CNS [KMT2A-rearranged B-acute lymphoblastic leukemia, is important in their CNS invasion. Other explanations can also be that rare blasts with higher ITGA6 levels can enter the CNS or that ITGA6 expression is elevated throughout the CNS infiltration process [CNS relapses are reported to be common in patients with t BCR-ABL1 (Ph+), 1 fusion . Ph+ leu1 fusion ,122. In  the CNS . Moreove process .ITGA6 has been shown to be elevated in tumor cells despite being expressed at low or undetectable levels in healthy tissues ,50,55. Vitga6 in lung adenocarcinoma and normal tissues acquired by The Cancer Genome Atlas and single-cell RNA-sequencing do not differ significantly [ITGA6-AS1 forms an RNA duplex with itga6 pre-mRNA, increasing the stability of itga6 pre-mRNA and reducing multiple myeloma cell invasion [However, various types of malignancies have varied integrin expression patterns, and even contradicting evidence for the same integrin can be discovered within the same cancer type . The mRNficantly . Furtherficantly  and multficantly . As a reinvasion .itga6 mRNA expression has been significantly associated with poor progression-free survival (PFS) and overall survival (OS) in ovarian cancer patients [itgb4 mRNA have a significant association with poor prognosis, metastasis, and resistance to platinum treatment. However, the heterodimeric partner itga6 strongly correlates with prognosis and lacks a significant correlation with metastasis and platinum resistance [itga6 mRNA expression in FIGO stage IV ovarian cancer solid tumors compared to stage III ovarian cancer, which was correlated with shorter overall survival [ITGA6 adhesion mediates drug resistance in ovarian cancer, indicating that its expression is upregulated in cisplatin-resistant cells [In the case of ovarian cancer, there is contradictory information regarding the expression of ITGA6 and its possible effect. Utilizing public datasets, ITGA6 is found to be a good prognosis predictor in ovarian cancer. Decreased patients . An extesistance . Givant–survival . On the survival . ITGA6 esurvival . ITGA6 ant cells .As previously indicated, both Thy1 and ITGA6 are potential markers of various cancer stem cells, and their expression is associated with poor differentiation, large tumor growth, lymph node metastases, high invasiveness, and shorter overall survival . In breaBecause the majority of CNS relapses occur in CNS-negative children, cytological testing of cerebrospinal fluid (CSF) is the gold standard for diagnosing CNS leukemia; however, its lower sensitivity compared to autopsy reports has also been shown ,94,95. TOn the other hand, the ITGA6-B isoform suppresses the cell cycle of colonic epithelial cells and is downregulated in colon cancer, whereas an up-regulation in ITGA6-A expression has been linked to a hyperproliferative phenotype ,28,139. itga6 showed a positive correlation with itga5 and itga3 [itga6 shows a negative correlation with infiltration levels of B-cells and T-CD8+ cells in head and neck cancer cells, while it is favorably correlated with T-CD4+ cells. No significant links have been discovered between ITGA6 and macrophages, neutrophils, or dendritic cell counts [itga6 expression, patients with HPV+ head and neck squamous cell carcinoma have a poor prognosis; however, itga6 expression levels have no effect on survival rates of HPV-negative head and neck squamous cell carcinoma patients [In head and neck malignancies, the expression of nd itga3 ,131. Thel counts . In situpatients .Drug resistance in tumor cells is developed by adaptive responses to external stimuli, the activation of specific pro-survival signals/antiapoptotic programs, the selection of drug-resistant subpopulations, and changes in microenvironmental properties ,55. Inteitga6 is a key drug-resistance gene [itga6 depletion inhibits Akt phosphorylation after radiotherapy [According to bioinformatics and experimental findings, nce gene . It suppnce gene ,73,136. nce gene ,143,144.nce gene ,137,144.nce gene . PI3K inotherapy . In addiotherapy .ITGA6 expression is linked to a group of survival genes, including birc5, mcl1, and xiap [itga6 sensitizes acute lymphoblastic leukemia cells to tyrosine kinase inhibitors (TKI) or chemotherapy. Even targeting ITGA6 alone promotes cell death [ll death . In concitga6. Finally, drug sensitivity is restored in EVI1-high leukemia cells treated using ITGA6-neutralizing antibodies or short hairpin RNA against evi1 [Treatment with the antibody against ITGA6 and P5G10 de-adhered acute lymphoblastic leukemia cells from the stroma and reduced stromal support in the face of chemotherapeutic damage . Additionst evi1 ,137,142.The condition under which clinical remission is established and remaining leukemia cells are detected using flow cytometry or polymerase chain reaction (PCR) testing is referred to as minimum residual disease . In precitga6, and it is linked to poor therapeutic response [itga6 is one of several genes overexpressed in B-acute lymphoblastic leukemia upon diagnosis, and it has been linked to the discovery of minimal residual disease later on [Cell adhesion is the most elevated gene network in quiescent/resistant and minimum residual disease, indicating that interactions with the microenvironment are involved in resistant phenotypes . One of response . In addilater on ,148,149.later on ,123,148,CDKN2A, CDKN2B, PAX5, IKZF1, BTG1, ERG, TP53, RB1, EBF1, and CRLF2, indicating that there is no correlation between itga6 and leukemia-related genes [itga6 at diagnosis is also linked to the existence of minimum residual disease at days 19 and 46 after chemotherapy induction but not linked to a genetic subtype [Evaluation of the genetic subgroups (KMT2A-rearranged (MLL), BCR-ABL1+ (Ph+), ETV6-RUNX1+ , hypodiploidy, and hyperdiploid) shows substantial differences in ITGA6 expression, despite the high frequency of its overexpression among cases of B-acute lymphoblastic leukemia in general . In KMT2ed genes . The ove subtype ,151.Notably, ITGA6 expression is negatively associated with white blood cell count, as is characteristic of the B-other cytogenetic leukemia category, which cannot be categorized into any of the known cytogenetic groups . In the All in all, integrin regulation is extremely complicated, and their function is defined by integrin activation and ligand affinity of specific integrin heterodimers rather than the amounts of individual integrin subunits. Therefore, it has been proposed that focusing on integrin affinity states is more likely to uncover the link between integrins and minimum residual disease rather than only focusing on integrin expression patterns .Autophagy is a highly conserved lysosomal degradation mechanism that is important for homeostasis, differentiation, development, and survival ,152. SomThe increased metabolic activity in cancer cells leads to increased ROS generation since these cells require energy and nutrients to maintain their high rates of cell growth and proliferation. ROS acts as a second messenger, triggering the activation of critical signaling pathways , as well as the production of HIF-1 for angiogenesis and autophagy genes, all of which are crucial regulators of cell proliferation, metabolism, survival, and cancer development. FLT3-ITD, JAK2, and Ras mutations increase ROS levels in acute myeloid leukemia cells, resulting in genomic instability and leukemogenesis. EVI1, an oncogenic transcription factor, increases survival and treatment resistance by inducing autophagy through elevated intracellular ROS. In leukemia, inhibiting autophagy improves chemosensitivity and tumor cell death . Nonetheitga6 gene has drastic effects [In addition to integrins being involved in crucial aspects of malignant progression, their expression patterns in neoplastic lesions differ from nonneoplastic tissues ,73. Ther effects ,18. In t effects . The tar effects .As there are pitfalls to finding an effective and safe therapy capable of inhibiting ITGA6 in vivo, and the functional blocking antibodies available may potentially cause important side effects if systemically administered because of its broad expression , anotherAs the roles of integrins in diseases are discovered, we have tried to achieve a further understanding of the mechanisms and signaling specific to individual subunits of different heterodimers. Therapeutic strategies could be made specific by targeting each subunit related to the particular situation. Meanwhile, the potential overlapping or compensating roles of integrin subunits need to be clarified and considered. In this review, we summarized the recent understanding of ITGA6’s function in various cancer types. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. ITGA6 is overexpressed in numerous types of malignancies, and its expression level is related to cancer development and poor survival in patients. In addition, its expression levels are closely associated with signs of epithelial-mesenchymal transitioning. Exosomal ITGA6 also implies metastatic organotropism. Thus, further understanding of these mechanisms could unravel new therapeutic opportunities that specifically target ITGA6 in certain cells and cancer types, which could lead to better clinical outcomes.


Abelmoschus manihot, and resveratrol. This review focuses on recent advances in the initiation, development, and therapeutic application of METTL3 in inflammatory diseases. Knowledge of the specific regulatory mechanisms involving METTL3 can help to deepen understanding of inflammatory diseases and lay the foundation for the development of precisely targeted drugs to address inflammatory processes.Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and autoimmune diseases have high incidence rates, still threaten human health, and represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis of various diseases. As the most widely discussed m6A methyltransferase, the pathogenic role of METTL3 in inflammatory diseases has become a research hotspot, but there has been no comprehensive review of the topic. Here, we summarize the expression changes, modified target genes, and pathogenesis related to METTL3 in cardiovascular, metabolic, degenerative, immune, and infectious diseases, as well as tumors. In addition to epithelial cells, endothelial cells, and fibroblasts, METTL3 also regulates the function of inflammation-related immune cells, including macrophages, neutrophils, dendritic cells, Th17 cells, and NK cells. Regarding therapeutic applications, METTL3 serves as a target for the treatment of inflammatory diseases with natural plant drug components, such as emodin, cinnamaldehyde, total flavonoids of  At thTimely shutdown of inflammation is crucial for physiological homeostasis , and dysRecent studies indicate that RNA modification of N6-methyladenosine (m6A) is critical for inflammation ; m6A desMETTL3 was the first m6A methyltransferase to be discovered. In 1997, Boker et al. isolated, purified, and sequenced METTL3  from HeLa cells, and confirmed that it is an important (N6-adenosine)-methyltransferase subunit . TogetheIn this review, we describe the role of METTL3 in macrophages, neutrophils, DCs, T helper (Th)17 cells, and natural killer (NK) cells which play crucial pathological roles in chronic inflammation. We comprehensively summarize METTL3 expression changes and related pathogenesis in inflammatory diseases, including atherosclerosis, myocardial infarction (MI), non-alcoholic liver disease, hyperuricemia (HUA), diabetes nephropathy, osteoarthritis (OA), intervertebral disc degeneration (IDD), rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), sepsis, pneumonia, and tumor. In conclusion, we focus on the therapeutic application of METTL3 in inflammatory diseases. Knowledge of the mechanisms by which METTL3 regulates inflammatory diseases will contribute to the development of improved targeted therapies and broaden clinical perspectives.22.1Inflammation involves multiple immune cells, among which macrophages are key participants. Macrophages/monocytes are derived from progenitor cells in the bone marrow and enter the bloodstream . After bMacrophages are plastic and, when stimulated by the microenvironment, can polarize into different phenotypes, which are generally divided into classic activated or inflammatory (M1) and alternate activated or anti-inflammatory (M2) macrophages . M1 macrSTAT1 transcript in macrophages, thereby elevating the levels of downstream inflammatory factors (PGC-1α) mRNA  mRNA . METTL3 esponses . Guo fouammation .NOD1) and receptor-interacting serine/threonine kinase 2 (RIPK2) mRNA, mediated by YTHDF2, thereby up-regulating levels of TNF-α, IL-6, and NO  mRNA degradation and promoted its expression. Microglia are often referred to as tissue-resident macrophages of the central nervous system . Neutrophils were considered to mainly be involved in acute inflammation, but it is now widely believed that neutrophils also have important roles in cancer, autoimmune diseases, and chronic inflammation . METTL3 pression .2.3CD40 and CD80 mRNA m6A modification levels, thereby promoting CD40 and CD80 expression , causing slower EGFR mRNA decay and increased EGFR expression  describes conditions ranging from steatosis and non-alcoholic steatohepatitis (NASH), which is characterized by lobular inflammation and hepatocellular injury, through to cirrhosis and hepatocellular carcinoma, as the disease progresses . Liver-sammation .3.2.2in vivo experiment, levels of inflammatory cytokines in the hippocampus of rats in the HUA group were significantly higher than those in the negative control group (HUA is a metabolic disease caused by raised serum uric acid (> 6.5–7 mg/dL) . Epidemiol group . Furtherol group . The latol group .3.2.3TIMP2) and downregulated its expression, which led to clear alleviation of inflammation and apoptosis via the Notch pathway in podocytes (PTEN) in podocytes was decreased under high glucose conditions , which affects renal fibrosis progression  through decreasing its m6A level, mediated by METTL3, thereby reducing inflammation and apoptosis of chondrocytes and inhibiting ECM degradation  mRNA stability, which induced apoptosis, inflammation, and senescence, as well as decreasing ECM synthesis in NPCs  is a chronic inflammatory autoimmune disease characterized by autoantibody production, synovial inflammation, cartilage damage, and bone erosion , 125. That model . METTL3 at model .3.4.2Psoriasis is a chronic, immune-mediated disorder, which can be provoked by non-specific triggers, such as mild trauma, sunburn, stress, infection , alcohol, or drugs . Briefly3.4.3UBE2L3, SLC22A4, TCF19, C6orf47, and SNAPC4 genes, suggesting that m6A methylation may contribute to IBD pathogenesis  mRNA and decreased GPX4 expression via accelerated degradation of GPX4 mRNA mediated by YTHDF2, with consequent ferroptosis of alveolar epithelial cells (SIRT1) mRNA in alveolar epithelial cells, leading to abnormal cell autophagy and deterioration of ARDS (Trim59 mRNA and activating the NF-κB pathway. CircN4bp1 up-regulated the expression of the enhancer of the zeste 2 polycomb repressive complex 2 subunit (EZH2) by combining with miR-138-5p, thus promoting M1 macrophage polarization and aggravating the degree of lung injury in ARDS mice  3/7 and the NF-κB signaling pathway, which induces the production of pro-inflammatory cytokines and interferon . Interfeand ISGs . Li et aand ISGs .Fungal keratitis (FK) is an aggressive infectious corneal disease caused by pathogenic fungi . METTL3 In addition, some studies of inflammation have been conducted using LPS-stimulated cells. METTL3 protein expression was elevated in LPS-induced retinal pigment epithelium cells, and silencing METTL3 increased the expression of nuclear receptor subfamily 2 group F member 1 (NR2F1) and promoted IL-6 secretion . Further3.6Chronic inflammation is a risk factor for tumor development, as it provides a microenvironment conducive to tumorigenesis, tumor development, and metastasis . A deep In addition, METTL3 regulates the infiltration of tumor-associated neutrophils. Silencing METTL3 caused papillary thyroid cancer cells to secrete more pro-inflammatory factors, particularly IL-8, which can recruit infiltration of tumor-associated neutrophils. The NF-κB pathway inhibitor, BAY 11-7082, inhibits IL-8 production by tumor cells and neutrophil infiltration, as well as inhibiting tumor growth .4The study of METTL3 expression changes and related pathogenic processes in inflammatory diseases provides clues for the development of effective drugs and informs novel diagnostic strategies Table 3.Ramulus cinnamomi, which has beneficial functions in lipid metabolism and inflammation of the liver (Abelmoschus manihot (TFA) have been used to treat kidney disease  mouse model . Cpd-564miR-1208 in hucMSCs-EVs reduced m6A levels in NLRP3 mRNA by down-regulating METTL3 expression in macrophages, which prevented NLRP3 inflammasome activation and exerted anti-inflammatory effects ;  effects .In addition, METTL3 may serve as a novel biomarker for RA diagnosis. Wang et al. found that increased METTL3 in RA patients was positively correlated with CRP and ESR ; however5The study of METTL3-mediated m6A modification brings new insights into the pathogenesis of inflammatory diseases. METTL3 is upregulated in most inflammatory diseases, indicating that it has pro-inflammatory effects; however, opposite expression trends in METTL3 expression have also been observed in the same diseases, including sepsis-related ARDS and OA, indicating that the effects of its expression may be related to cell type, modeling methods, disease status, or other potential regulatory factors. Moreover, METTL3 can regulate different target genes in the same disease, which challenges the accuracy and safety of drug development. In addition, METTL3 can regulate macrophage M1 polarization, implying that METTL3 is a potential therapeutic target in macrophage-related diseases. As METTL3 can regulate the infiltration and polarization of TAMs and tumor-associated neutrophils, it is meaningful to study the therapeutic application of METTL3 in anti-tumor immune responses. There have been promising studies of natural drugs targeting METTL3 in the treatment of inflammatory diseases, although their detailed pharmacological effects are not yet fully understood. Whether agents targeting METTL3 are natural plant-derived ingredients, chemically synthesized drugs, or biological agents, their therapeutic prospects warrant further research.BS conceived and drafted the manuscript. BS and YZ designed and drew the figures. YC, JZ, and CX assisted in searching and sorting articles. YP and XZ reviewed and provided suggestions for the manuscript. JL reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.


Stress has become a universal biological phenomenon in the body, which leads to pathophysiological changes. However, the molecular network interactions between endoplasmic reticulum (ER) stress and ferroptosis under stressful conditions are not clear. For this purpose, we screened the gene expression profile of GSE173795 for intersection with ferroptosis genes and screened 68 differentially expressed genes (DEGs) , mainly related to lipid and atherosclerosis, autophagy—animal, mitophagy—animal, focal adhesion, DNA replication, proteasome, oocyte meiosis, toll-like receptor signaling pathway, cell cycle, etc. Immune infiltration analysis revealed that stress resulted in decreased B cells memory, T cells CD8 and T cells CD4 memory resting, monocytes, macrophages M2, and increased B cells naive, T cells follicular helper, and macrophages M1. 19 core-DEGs  were screened, all of which were up-regulated DEGs. These biological processes and pathways were mainly involved in responding to ER stress, lipid and atherosclerosis, cellular response to stress, cellular response to chemical stress, and regulation of DNA-templated transcription in response to stress, etc. Spearman analysis did not find MAPK14 to be significantly associated with immune cells. Other core-DEGs were associated with immune cells, including B cells naive, T cells follicular helper, and monocytes. Based on core-DEGs, 283 miRNAs were predicted. Among the 22 miRNAs with highly cross-linked DEGs, 11 had upstream lncRNA, mainly targeting STAT3, SP1, CDKN1A, and SIRT1, and a total of 39 lncRNA were obtained. 85 potential drugs targeting 11 core-DEGs were identified and were expected to be potential immunotherapeutic agents for stress injury. Our experiments also confirmed that Liproxstatin-1 alleviates common cross-linked proteins between ER stress and ferroptosis. In conclusion, our study explored the molecular mechanisms and network interactions among stress—ER stress—ferroptosis from a novel perspective, which provides new research ideas for studying stressful injury. These deregulate the redox balance of the endoplasmic reticulum (ER), leading to the accumulation of unfolded or misfolded proteins in the ER, triggering ER stress, and activating the body's unfolded protein reaction (UPR)  Affymetrix Mouse Genome 430 2.0 Array. It was used to investigate the gene expression difference during ER stress (tunicamycin (TM) induced) in mice. Three control samples and four stressed samples of wild type (WT) mice were selected, totaling seven. We also collected 288 ferroptosis genes from the FerrDb database , and the heat map of the common DEGs expression was drawn with HemI 2.0.GEO2R analysis tool was employed to compare the gene expression profiles of stressed samples and controls samples to obtain DEGs. The DEGs meeting |logFC| > 1 and https://david.ncifcrf.gov/home.jsp) to systematically annotate the biological functions of DEGs. Select gene ontology (GO) function analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, with p-value <0.01 and FDR < 0.01 statistically significant. The analysis items include biological process (BP), molecular function (MF), cell component (CC), and signal pathway. Subsequently, we also used gene set enrichment analysis (GSEA) to conduct pathway enrichment analysis on DEGs, screen enrichment pathways with p-value and adjust p-value less than 0.01, and select the top six.We use the database for annotation, visualization and integrated discovery (DAVID) database (https://cibersortx.stanford.edu/) for immune infiltration analysis. The analysis conditions were set as follows: signature matrix file: LM22; permutations for significance analysis: 1000; check “enable batch correction”. According to the screening results of p-value <0.05, the immune cell types that did not participate were eliminated. Draw the composition diagram of immune cells in each sample, the differential expression diagram of immune cells in the control group and the stress group, and the correlation diagram of immune cells. Meanwhile, principal component analysis (PCA) analysis was performed to verify whether the stress group could be distinguished from the control group based on the difference in immune cell infiltration.To confirm the correlation between ER stress and immune cells, the expression data of GSE29929 were uploaded to the CIBERSORTx (https://string-db.org/), and then the core-DEGs were screened using the molecular complex detection (MCODE) function of Cytoscape 3.9.1 software. The setting conditions of the MCODE application were: degree cutoff = 2, node score cutoff = 0.2, k-core = 2, max.depth = 100. Upload the screened core-DEGs to the DAVID database for GO function and KEGG pathway analysis. Also, Metascape (http://metascape.org/gp/index.html#/main/step1) was employed to re-identify the BP and pathway enrichment of core-DEGs, and the top 20 were selected on the premise of p-value <0.01. Finally, PCA analysis verified whether the stress and control groups could be identified based on the expression difference of core-DEGs.The protein–protein interaction (PPI) network diagram was constructed by the STRING tool  to predict that core-DEGs target key miRNAs, and cross the prediction results of MiRTarBase and miRWalk databases to ensure the accuracy of the results. The screening results were based on p-value <0.05, the seed sequence length was greater than 7, and the target gene binding region was 3′UTR. The CC, MF, BP, and biological pathway of miRNA were enriched and analyzed by Funrich software. Subsequently, StarBase v2.0 (https://starbase.sysu.edu.cn/) was used to identify the upstream molecules lncRNAs of miRNA, and the highest reliability was selected as the standard to analyze the core-DEGs–miRNA–lncRNA interaction network.We use miRWalk 3.0 (https://dgidb.org/) of gene–drug interactions to identify potential therapeutic drugs (preset filters check “approved” and “immunotherapies”) and display the interactions between drugs, genes, and immune cells.Based on the core-DEGs, we use the DGIdb database  from 19 core-DEGs for validation in the mouse model.Animal model construction: 20 C57 mice  at 6–8 weeks were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. with the certificate number SCXK (Beijing) 2021-0006. Adaptive feeding for 7 days, free diet and drinking water, 12 hours light–dark cycle rhythm, temperature 20°C–25°C, humidity 50 ± 5%. This study was approved by the Laboratory Animal Management Committee of Hebei Medical University, making every effort to reduce the number of animals and minimize pain and suffering. They were randomly divided into four groups: control group, TM group, TM + Liproxstatin-1  group, Lip-1 group, with five mice in each group. TM of 1 mg/kg was injected intraperitoneally in the TM group; in the TM + Lip-1 group, 10 mg/kg Lip-1 was injected again 1 hour after intraperitoneal injection of 1 mg/kg TM; Lip-1 group received intraperitoneal injection of 10 mg/kg Lip-1; the normal group was given the same amount of normal saline. All groups were put to death after neck dislocation 24 hours after injection, and the left lobe of liver tissue was extracted and stored in 4% formaldehyde.μm serial sectioning, routine hematoxylin eosin (HE) staining, neutral resin sealing, and Aperio ScanScope CS2 scanner  was used to observe the pathological changes. Immunohistochemical verification of four proteins, namely ATF4, EIF2S1, HSPA5, MAP3K5, and three slices of each protein on each paraffin-embedded block, drying in a 60°C incubator, dewaxing to water, antigen repair, endogenous peroxidase blocking, goat serum blocking, antibody (1 : 100) incubation overnight at 4°C, reaction enhancement solution incubation for 40 minutes at 37°C, enhanced enzyme labeled goat anti-mouse/rabbit immunoglobulin G (IgG) polymer incubation for 40 minutes at 37°C, 3,3′-diaminobenzidine (DAB) coloration, hematoxylin re-staining, and film sealing. Aperio ScanScope CS2 scanner was employed for observation, and color deconvolution V9 software was selected for statistical analysis based on average positive intensity.Histopathology and immunohistochemistry: fixed liver tissue, dehydrated by ethanol, transparent by xylene, paraffin embedding, 4 We screened 4853 DEGs (3954 up-regulated and 899 down-regulated) from GSE29929 during ER stress in mice, and 68 common DEGs (63 up-regulated and 5 down-regulated) were screened after crossing with the ferroptosis gene , Table 1p-value are cellular response to glucose starvation, positive regulation of transcription from RNA polymerase II promoter, positive regulation of transcription from RNA polymerase II promoter in response to ER stress. MF has 13 aspects, mainly focusing on protein kinase binding, transcription regulatory region sequence-specific DNA binding, transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding, etc. CC involves nine aspects, including cytosol, RNA polymerase II transcription factor complex, nucleoplasm, cytoplasm, chromatin, euchromatin, pre-autophagosomal structure, nucleus, and lipid particle. The enrichment results of the KEGG pathway are shown in 68 DEGs were uploaded to the DAVID, of which 67 were successfully used for GO function analysis and 54 were successfully used for KEGG pathway enrichment analysis. The results of the GO function analysis are shown in R = 1). The competition effect of dendritic cells resting and NK cells resting was the significant (R = −0.94). Unfortunately, based on the infiltration of immune cells in liver tissue, PCA analysis results showed that P = 0.313, R = 0.111, which failed to distinguish the control group from the stress group -ATF4 pathway inhibited ferroptosis by upregulating HSPA5, system Xc-, and other molecules [Since the lab of Dr. Brent R. Stockwell proposed ferroptosis as a form of cell death in 2012 , the mecolecules , 23. On olecules , 24. In olecules . Studiesolecules , 27, butα–ATF4–CHOP pathway, was closely related to ferroptosis. Xu et al. observed iron deposition, lipid radical accumulation, and mitochondrial shrinkage in a mouse model of ulcerative colitis (UC), and also found that the PERK–ATF4–CHOP pathway was significantly activated in the colonic epithelium of UC mice, and that treatment with GSK414, an inhibitor of the ER stress PERK pathway, significantly inhibited the process of ferroptosis [α pathway, and ferroptosis pathway in human bronchial epithelial cells, and sequencing results showed that the activation of ER stress promoted the occurrence of ferroptosis [Our study screened 68 common DEGs for ferroptosis and ER stress using bioinformatics techniques, accounting for approximately 26.255% (68/259) of all ferroptosis genes, suggesting that the ferroptosis pathway may play an important role during ER stress. Through PPI network analysis, we screened 19 up-regulated core-DEGs, and their BP and pathways mainly involved in response to ER stress, lipid and atherosclerosis, cellular response to stress, cellular response to chemical stress, and regulation of DNA-templated transcription in response to stress, etc. Immune cell infiltration analysis revealed a predominance of monocytes, NK cells activated, macrophages M1, T cells CD4 memory resting, and macrophages M0, which is consistent with the pathological changes observed microscopically with focal inflammatory cell infiltration visible between the interstitial spaces of liver tissue. Lip-1 injection significantly attenuated TM-induced inflammatory cell infiltration, cell cord disorder, and hepatocyte apoptosis, but the TM + Lip-1 group still had altered damage and did not fully return to normal compared to the control group, suggesting that there is a partially synergistic pathway between ferroptosis and ER stress, not all of it. From the core-DEGs screened, the ER stress response, especially the PERK–eIF2roptosis . It is wroptosis . Under troptosis . It suggroptosis .α [α pathway, and ferroptosis pathway-related proteins in CSC treated BEAS-2B cells , the levels of MAP kinase activation , and p-JNK)-related proteins were also significantly enhanced [2+, lipid peroxidation, GSH depletion, up-regulation of HMOX1, and heme degradation to Fe2+ in endometrial carcinoma cells, and also participates in inducing autophagy and inhibiting cell migration and ER stress, which may be a new marker for cancer treatment [α in a BON-1 cell line whose sensitivity to ART treatment is associated with long-term differential regulation of p21 (CDKN1A) [In 19 core-DEGs, in addition to the above crosstalk molecules common to ER stress and ferroptosis, deletion of Bp65 (RELA) was found to significantly up-regulate ferroptosis and exacerbate colitis in IEC-specific NF-kappa Bp65 deficient mice, and phosphorylated Bp65 significantly inhibited ER stress by binding eIF2α . In addienhanced . Juglonereatment . Tagitinreatment . Artesun(CDKN1A) . Alim et(CDKN1A) . HoweverIn summary, the study of molecular network interactions between ER stress and ferroptosis has received increasing attention from researchers in various fields, but stress injury can be caused by a variety of risk factors, with complex symptoms, complex psychological and physiological basis, and is prone to the combination of other injuries and diseases, making it difficult to study the interactions between the two. We try to screen biomarkers and molecular targets related to stress injury by multi-omics  and bioinformatics techniques, which are helpful to study the crosstalk between ER stress and ferroptosis in stress injury, and can form a molecular network related to ER stress and ferroptosis, which is more helpful to elucidate the mechanism of stress injury and establish a personalized stress diagnosis system.Here, we used bioinformatics technology to screen the intersecting DEGs of ER stress and ferroptosis under stress conditions and analyzed the occurrence, development process, and molecular mechanism of stress injury involved in DEGs, focusing on the linkage between ER stress and ferroptosis. It makes up for the lack of research on the molecular network mechanism of ER stress and ferroptosis in stress injury, and explores the mechanism of stress—ER stress—ferroptosis and molecular network interactions from a novel perspective, which provides a new theoretical basis for the study of stress injury.