BRCA1/2, HER2, PTEN, PIK3CA, CTNNB1, RAS, CTNNB1, FGFR, TP53, ARID1A, and TERT) affect the mitochondria, highlighting the possible associated individual therapeutic targets. With this approach, drugs targeting mitochondrial glucose or fatty acid metabolism, reactive oxygen species production, mitochondrial biogenesis, mtDNA transcription, mitophagy, or cell death pathways could provide further tailored treatment.There is an increasing understanding of the molecular and cytogenetic background of various tumors that helps us better conceptualize the pathogenesis of specific diseases. Additionally, in many cases, these molecular and cytogenetic alterations have diagnostic, prognostic, and/or therapeutic applications that are heavily used in clinical practice. Given that there is always room for improvement in cancer treatments and in cancer patient management, it is important to discover new therapeutic targets for affected individuals. In this review, we discuss mitochondrial changes in breast and gynecological  cancers. In addition, we review how the frequently altered genes in these diseases ( The role of mitochondria in solid tumors has been widely investigated in the last decade, along with their contribution to the development and progression of hematologic malignancies ,4,5,6,7.In clinical practice, cancer patients often undergo molecular and cytogenetic studies to determine the appropriate targeted therapy and to provide prognostic data . Our undBRCA1/2, HER2, PTEN, PIK3CA, CTNNB1, RAS, CTNNB1, FGFR, TP53, ARID1A, and TERT). There are many more genes that are associated with the development or progression of these tumors; here, we will only discuss selected genes with their effects on mitochondria. For more details on mitochondria-related cellular metabolism, apoptosis regulation, mitochondrial dynamics, mitophagy, and mitochondrial trafficking, along with information on the mitochondrial DNA (mtDNA) and mtDNA transcription machinery in general, please see our previous article ..21].Anaerobic glycolysis. In cancer cells, pyruvate is abundantly transformed into lactate by anaerobic glycolysis , with thEnolases. Enolases catalyze the conversion of 2-phosphoglycerate to phosphoenolpyruvate. These enzymes are typically located within the cytosol, yet they tightly associate with the mitochondrial surface [ surface . In huma surface . In BC,  surface .Pyruvate kinase. Pyruvate kinase (PK) is a rate-limiting glycolytic enzyme that converts phosphoenolpyruvate to pyruvate with the generation of one ATP molecule. It has two isoforms, PKM1 and PKM2, which are encoded by the same gene and are generated by alternative splicing. PKM1 is found mainly in normal cells, whereas PKM2 is an embryonic isoform that is expressed in cancer cells [er cells . Elevateer cells .Oxidative phosphorylation (OXPHOS) markers. According to the Warburg hypothesis, the increased rates of anaerobic glycolysis that are observed in tumor cells might be due to their impaired respiratory capacities . ReducedOther metabolic markers. Among the numerous cancer markers in mitochondria, hydratases, dehydrogenases, and oxidases play crucial roles in BC pathogenesis.Hydratases. The NAD-dependent bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD) regulates the biosynthesis of tetrahydrofolate, providing precursors for nucleotides and methylation reactions. The MTHFD2 protein content is 3-fold decreased in BC lines [BC lines .Dehydrogenases. Isocitrate dehydrogenases (IDHs) are important players in the exchange of metabolites within the cell, and two IDH isoforms can be found within the mitochondrion. IDH2, an NADP-dependent enzyme, has a role in the shuttling of electrons between the mitochondrion and the cytosol. IDH3 is an NAD-dependent mitochondrial matrix enzyme that is involved in the TCA cycle. BC cell lines display high levels of IDH2, and its expression is positively associated with overall survival in BC patients [patients , possiblOxidases. Coproporphyrinogen III oxidase (HemN), an enzyme required for heme synthesis, is present in the inner mitochondrial membrane. Its expression is increased in Adriamycin-resistant BC cells [BC cells .In mtDNA is particularly susceptible to mutations due to its proximity to ROS generation and the relatively inefficient mtDNA repair system . The fremtDNA and breast tumorigenesis. For a great review on this topic, see, for example, Yadav and Chandra [ Chandra . In the  Chandra ,57,58,59 Chandra . An mtDN Chandra . Mutatio Chandra ,63,64, w Chandra ,66,67. AGermline mtDNA mutations. BC cells, like other cancer types, commonly harbor instability in the mitochondrial genome [l genome ,69,70,71l genome . The 103l genome ,59 and il genome ,59,73,74l genome . Chronicl genome . Whetherl genome ,73. mtDNl genome , along wl genome . An anall genome .Somatic mtDNA alterations. Despite the fact that numerous germline mutations have been linked to breast tumorigenesis, the majority of BCs are not inherited. In sporadic BC cases, somatic mtDNA mutations may lead to the selective transformation of breast epithelial cells and tumorigenesis. Various somatic mtDNA mutations have been detected in BC [ed in BC ,84,85,86mtDNA displacement loop alterations (erations . The D-lDeletions. Deletion of 4977 base pairs (ΔmtDNA4977 mutation) has been found in BC tissue, but it was also detected in the surrounding normal breast tissue—indicating either the premalignant state of the tissue exhibiting normal morphology, or representing a clinically non-significant alteration ,91. In a5.Alterations in mtDNA abundance. Mitochondria have multiple copies of mtDNA, and this copy number changes in response to energy demands, with both increased and decreased mtDNA content previously reported in cancer cells [ND1 gene primers [er cells ,95. In t primers .Interestingly, the circulating mitochondrial nucleic acid copy number could be used as a prognostic marker for BC. Patients with lower mtDNA copy numbers have better disease-free survival than patients with high mtDNA content when treated with anthracycline after surgery , likely UQCRFS1, encoding complex III proteins, can be amplified [Nuclear-DNA-encoded proteins are also an integral part of the OXPHOS system, and conversely, defects in OXPHOS induce irreversible changes in the nuclear genome ,98,99. Mmplified . DNA polmplified .Mitochondrial respiration constitutively produces ROS, and OXPHOS dysfunction further increases their generation. In cancer cells, a further increase in ROS can be observed.ROS damage control. NADPH oxidase 1, a major source of ROS in cells, predominantly localizes to the mitochondria and is highly expressed in breast (86%) tumors [) tumors . To coun) tumors . A histo) tumors .HSP90 family. Members of the HSP90 gene family are considered essential regulators of protein folding. TNF receptor-associated protein 1 (TRAP1) is a member of the HSP90 family and is considered mostly mitochondrial. In vivo studies in rats have shown that TRAP1 protects against hypoxia by reducing the generation of ROS, improving mitochondrial complex IV activity, and preserving ATP levels [P levels . TRAP1 eP levels . There iP levels . This inP levels . TRAP1 hP levels .Small HSP family. HSP27 is mainly cytosolic, but a small fraction localizes to the mitochondria. HSP27 expression may function as a useful prognostic marker of poor survival in many human cancers. HSP27 is upregulated in the serum of BC patients [patients  and corrpatients .Mitochondrial function is generally dependent on the import of cytosolic proteins. Complex protein structures form channels that translocate preproteins from the cytosol to the mitochondrial matrix. The proteins that constitute these channels are the translocase of the outer mitochondrial membrane (TOMM) and translocase of the inner mitochondrial membrane (TIMM) . InteresTranslocator protein (TSPO), also known as peripheral-type benzodiazepine receptor, is a well-conserved protein located at OMM-IMM contact sites and is closely associated with VDAC and ANT. TSPO has been shown to participate in apoptotic processes but has been described as having both anti- and proapoptotic properties. The overexpression of TSPO is associated with aggressive tumor subtypes in breast carcinomas and correlates with advanced stages of malignancy. Metastatic breast adenocarcinomas manifest increased TSPO expression relative to their primary malignancies .Increasing evidence shows the involvement of mitochondrial dynamics in cancer development, but structural mitochondrial alterations appear to be heterogeneous and nonspecific to neoplasias. There is an increased mitochondrial mass in BC , with a TP53, BRCA1, BRCA2, PTEN, ATM, CDKN1B (coding protein p27), SKP2, and RAD51, are well-known TSGs involved in DNA repair and other cellular mechanisms [BRCA1 and BRCA2 genes , widely known genetic markers of hereditary breast cancer (HBC). Based on their functions, other similar genes were suspected, and some were later proven, to act as predisposing factors in BC [BRCA1/2 gene function in the DNA damage response pathway eventually led to the identification of a discrete number of susceptibility genes, including ATM, BRIP1, CASP8, CHEK2, NBN, PALB2, PTEN, TP53, and STK11 [Besides environmental factors, many genetic settings (intrinsic factors) have been proven to drive BC initiation and progression . Similachanisms ,129. Thers in BC ,131,132.nd STK11 ,137,138.PUM1, B2M, ACTB, RPL13A, LDHA, and NONO, regulate basic cellular functions governing or preventing cell growth. Their mutations therefore promote cell proliferation [AKT1, GATA3, PIK3CA, and MAP3K1 [CBFB and RUNX1 have also been described among somatic mutations in BC. Deletion or translocation events in tumor suppressor genes, such as AKT3 and MAGI3, have also been associated with breast tumorigenesis. Recent studies on BC driver genes uncovered an additional list of genes involved in tumorigenesis, including CCND1, ERBB2, FGFR1, MYC, PIK3CA, PTEN, GATA3, MAP3K1, and RB1 [Besides tumor suppressors, housekeeping genes, such as feration . In BC, feration . Most offeration . Besidesd MAP3K1 ,144,145. and RB1 ,146,147.In this part of the review, we summarize the participation of selected well-known and common somatic mutations that influence breast tumorigenesis via mitochondria and mitochondrial metabolism. In addition, some of the genes involved in breast tumorigenesis are also important in EC and/or OC and will be discussed in those sections.BRCA1 gene, when harboring germline mutations, confers a high susceptibility to breast and ovarian cancer predisposition and may account for a total of 10% of the BC incidence [BRCA1/2 genes have been found in individuals with a family history of BC [BRCA1/2 genes, however, account only for ~40% of familial BC cases, with a wide cohort of subjects harboring wild-type BRCA1/2 genes [The ncidence   polymerase (PARP) inhibitors of single-strand break repair, compensating for the lack of HR [BRCA1 expression is regulated by the ubiquitin–proteasome system, which involves several E3 ubiquitin ligases, including HERC2, HUWE1, and FBXO44 [BRCA1 is degraded in response to the loss of mitochondrial membrane potential. This proteasomal degradation is dependent on PINK1 and partly mediated through the E3 ligase Parkin. This BRCA1 degradation causes DNA double-strand breaks. Strikingly, BRCA1 and PINK1/Parkin expression are inversely correlated in cancerous mammary glands from BC patients. BRCA1 knockdown represses cancer cell growth, and high BRCA1 expression predicted poor relapse-free survival in BC patients. These observations indicate a novel mechanism by which mitochondrial damage is transmitted to the nucleus, leading to BRCA1 degradation [DNA double-strand break repair by homologous recombination (HR) is one of the primary mechanisms by which ck of HR ,160. Addd FBXO44 ,164,165.d FBXO44 . PINK1  is an oncogene that is overexpressed in many types of cancers , and its activation correlates with a poor prognosis [rognosis . It was rognosis ,184,185.rognosis ,187,188.rognosis . It is wrognosis . See alsPTEN) will be discussed in more detail in PTEN, given its relevance in BC, as a driver gene [Phosphatase and tensin homolog , is a malignant epithelial neoplasm originating from the endometrium. Based on its morphology, it can be further divided into different histologic types, such as endometrioid carcinoma, clear-cell carcinoma, serous carcinoma, carcinosarcoma, squamous cell carcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, and others .Histology. Endometrioid EC is the most common type of adenocarcinoma, which has glandular growth with variable architectural patterns, with areas of possible squamous or other differentiation. Grading is based on its architectural complexity, dividing it into low-grade (grades 1–2) and high-grade (grade 3) tumors. The pathophysiology of this type of carcinoma is driven by estrogen that is unopposed by progesterone or progestin. This unopposed estrogen alters the transcription profile of epithelial cells via estrogen receptors (ERs) that directly bind to DNA  classification. This classification divides these tumors into four molecular subtypes [POLE gene , have a better prognosis than other groups.Ultramutated (polymerase ε (POLE) mutant): mostly composed of endometrioid ECs, which, despite having an increased mutation frequency and hotspot mutations in the MLH1 silencing due to hypermethylation. In general, tumors in this group are associated with intermediate, stage-dependent prognosis.Hypermutated (mismatch-repair-deficient (MMRd)): Involves germline and somatic mutations, resulting in microsatellite instability, such as via TP53 alterations are present, with ~50% of cases being serous carcinomas and carcinosarcomas, and ~25% of cases are higher-grade endometrioid ECs. In general, tumors in this group are associated with inferior survival.Copy number high : TP53 and POLE wild-type and MMR-proficient tumors, which frequently harbor PTEN, PIK3CA, ARID1A, or KRAS alterations. The majority of these tumors are low-grade endometrioid ECs [Copy number low (no specific molecular profile (NSMP)): This group includes ioid ECs .subtypes ,197:UltrPLOE-mutated and MMR-deficient groups have been shown to have better outcomes, even in the grade 3 EC group [FGFR2 mutations exhibiting poorer outcomes [For recurrence-free survival, EC group . In addioutcomes . Currentoutcomes ,201,202.Here, we discuss EC and its common genetic alterations in relation to mitochondria.Changes in OXPHOS. Many mitochondrial and metabolic changes have been identified in EC, with several attributed to estrogen effects in type I ECs. EC is thought to be a “high OXPHOS” cancer, meaning that, unlike many other tumors showing mostly increased glycolysis, EC heavily relies on OXPHOS [TP53-deficient EC, which is associated with a poor prognosis [n OXPHOS . This warognosis .ATP5IFE expression, coding a subunit of complex V) in EC cells is associated with better disease outcomes, a lower grade, and a lower stage of EC, along with endometrioid histology [In vitro and in vivo MMRd-deficient EC models revealed impaired mitochondrial function, decreased basal oxygen consumption, and the decreased expression of 32 genes related to electron transport chain function . In typeistology , promptiAnaerobic glycolysis. In addition, increased anaerobic glycolysis  has been reported in EC, with multiple reports linking the glycolysis-associated gene or long noncoding RNA signature to poorer EC patient outcomes [outcomes . In addioutcomes ,208.mtDNA copy number changes. An increase in mitochondrial mass and a two-fold increase in the mtDNA copy number have been identified in endometrioid EC. Serous EC was also found to have an increased mtDNA copy number in a previous study [us study . Interesus study . Enhanceus study ; howeverus study . In addius study ,213.mtDNA mutations. Both somatic and germline mutations in mtDNA have been identified in the early (~9%) and late (~12%) stages of ECs, with some mutations being tumorigenic and some being adaptive [nd late ~2% stagesadaptive ,214.Germline mtDNA mutations. Germline mtDNA mutations in EC frequently involve the D-loop region, with point mutations such as m.16189t>C commonly identified in endometrioid EC [ND2 (m5178A>C), coding the NADH dehydrogenase 1 enzyme [COI (m.7028C>T), coding cytochrome oxidase subunit I [rioid EC . In addirioid EC . Additio1 enzyme , or COI ubunit I , have alSomatic DNA mutations. As for somatic mtDNA mutations in EC, several studies have shown polymorphisms in the D-loop area, in the rRNA-coding area, and in one of the mitochondrial complex protein-coding areas—summarized in an excellent recent review article [ article . Interes article .PTEN in healthy tissues and tumorigenesis. The phosphatase and tensin homolog (PTEN) tumor suppressor gene is found in most human tissues. It regulates transcription, translation, and cell cycle progression, among other processes. In short, it prevents cells from proliferating too rapidly or in an uncontrolled manner. In both heritable and sporadic cancers, the loss of function of PTEN results in genomic instability, cell proliferation and growth, increased cell survival, defective DNA repair, cell migration and adhesion, angiogenesis, and cellular metabolism. Its main downstream target is the PI3K/AKT/mTOR pathway; however, it has other non-enzymatic effects (see later in this section) [section) ,220,221.PTEN deletion or inactivation acts as a positive regulator of the PI3K/AKT/mTOR pathway, mainly via PIP3 accumulation due to a lack of dephosphorylation, which ultimately inhibits apoptosis [The PTEN protein has both lipid phosphatase and protein phosphatase activities. The lipid phosphatase activity is associated with the arrest of G1/S cell cycle progression, whereas the protein phosphatase activity is associated with growth-factor-stimulated MAPK signaling inhibition, cellular adhesion, spreading, and migration. The combined losses of both lipid and protein phosphatase activities result in tumorigenesis with cellular senescence, apoptosis escape, aberrant cell growth, and increased cell spreading and migration . PTEN’s poptosis .Besides its phosphatase activities, PTEN also has non-enzymatic roles: it acts as a scaffolding protein in the nucleus and in the cytoplasm, with the protein having a tumor suppressor function when present in the nucleus. The various PI3K-dependent and PI3K-independent downstream effects make PTEN a major regulator of cell survival and function ,223,224.The role of PTEN in mitochondria. To maintain genomic stability, PTEN acts through its phosphatase-independent (non-enzymatic) function as a scaffolding protein [PTEN overexpression was shown to inhibit mitophagy via blockage of the Toll-like receptor 4 (TLR4)–c-JUN N-terminal kinase (JNK)–BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) pathway. In addition, PTEN-long (PTEN-L), a PTEN isoform, when located at the outer mitochondrial membrane, dephosphorylates ubiquitin to inhibit mitophagy. Moreover, cytosolic PTEN can also suppress mitophagy by targeting the fusion protein Mfn2 and Rab7A (involved in endocytosis). PTEN has a complex role in mitophagy and may be influenced by the microenvironment, the cellular state, and even the cell type [ protein . In addi protein . Additio protein ,229,230.ell type ,232.PTEN loss and cellular metabolism. The effect of PTEN loss on cellular metabolism is also complex, ultimately leading to improved insulin sensitivity, providing a survival advantage for tumor cells through an improved ability to handle metabolic stress. These effects are either via PI3K/AKT signaling or are independent of it. It has been shown that PTEN loss leads to the increased phosphorylation of certain mitochondrial  and glycolytic proteins , leading to increased glycolysis. Additionally, gluconeogenesis is inhibited by PTEN loss via AKT induction, which results in the inhibition of the two rate-limiting enzymes, glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Cellular respiration is induced by the upregulation of PI3K/AKT due to its regulation of ERR and NRF, two mitochondrial biogenesis regulators. Moreover, AKT mobilizes the glucose transporter GLUT4 to the cell membrane, which is normally regulated and inhibited by PTEN [ by PTEN . PTEN lo by PTEN ,233. LipPTEN inactivation occurs via gene deletions, gene mutations , and epigenetic or transcriptional alterations [erations ,235. In erations .The role of PTEN in female cancers. In the female population, PTEN has been shown to be one of the most frequently mutated genes (13%) in the four most frequent female cancers: breast, ovarian, endometrial, and cervical cancers [ cancers ,238. The cancers ,240.PTEN mutations can co-exist with other gene mutations and lead to aberrant PI3K/Akt/mTOR pathway activation. For example, the combination of PTEN mutations with KRAS mutations in the ovary has been shown to induce invasive and widely metastatic endometrioid OC [rioid OC .PTEN in the fallopian tube is one of the multiple genetic modifications that induce tumorigenesis [PTEN leads to multicellular tumor spheroids in the fallopian tube epithelium. Tumor spheroids are associated with tumor survival under ultra-low-adhesion conditions, tumor attachment to the extracellular matrix exposed during ovulation, and the colonization of tumor cells in the ovary, possibly contributing to high-grade serous OC’s seeding phenomenon in ovaries [Several published preclinical models suggest that the loss of igenesis . A recen ovaries .PTEN-altered tumors by taking away their metabolic advantage. Inducing mitophagy could also hold therapeutic potential, but more research is required before therapies are going to be available.In addition, inhibiting glycolysis, lipogenesis, or mitochondrial biogenesis would possibly be additional drug targets in patients with PTEN-related changes summarized in See the PI3K pathway. The phosphatidylinositol-3 (PI3) kinase (PI3K) pathway, discovered in the 1980s, consists of a family of lipid kinases that are categorized into three distinct classes  based on their structure and substrate specificity [PIK3CA is a proto-oncogene that encodes the class I catalytic subunit (p110α) of PI3K; it is also known as the p110α protein. Its downstream target, the serine/threonine kinase mammalian target of rapamycin (mTOR) enzyme, is the main effector of this pathway. With the increased expression of PIK3CA, mTOR is constantly activated, leading to accelerated cell growth, motility, survival, proliferation, protein synthesis, autophagy, intracellular trafficking, and angiogenesis [PTEN mutations; however, PTEN mutations also have PI3K-independent alterations  and inhibiting the expression of some autophagy proteins (via FoxO transcription factor inhibition). When high levels of ROS are present, however, AKT can induce beclin1-dependent autophagy. Importantly, PTEN is a negative regulator of the PI3K/AKT pathway [PTEN, the effect of the PI3K/AKT/mTOR pathway on autophagy is not completely understood. pathway . In addi pathway . SimilarPI3K in mitochondria. Furthermore, inhibiting PI3K and mTOR can block tubulin polymerization, which leads to microtubule disturbances [urbances , likely urbances . In conturbances .PI3K/AKT/mTOR pathway in BC, EC, and OC. The PI3K/AKT/mTOR pathway is one of the most studied intracellular signaling pathways through extensive genomic analysis using molecular profiling by The Cancer Genome Atlas. It helped to identify some of the most common alterations involving metabolic and signaling pathways, especially in OCs (~12%). PIK3CA mutations can also be found in BC (~8–40%) and EC (~36% and ~53 endometrioid ECs), among others. In EC, mutations in exon 9, specifically charge-plus changing substitutions, are more likely to lead to the decreased survival of patients with endometrial carcinoma [PIK3CA alteration rate was found to be 45.42% in endometrial carcinoma, 16.31% in ovarian epithelial tumors, 26.37% in cervical cancers, 19.01% in vulva carcinoma, and 40.35% in uterine carcinosarcoma [PIK3CA mutations have also been shown to drive therapy resistance in epidermal growth factor receptor 2 (EGFR2)-positive BC [arcinoma . Mutatioarcinoma . Using aosarcoma ,240,249.itive BC .PIK3CA-related changes summarized in Mitochondrial targeting may add to the repertoire of drug selection in PI3K/AKT/mTOR-associated tumors based on their metabolic and other mitochondria-related effects. See the The role of KRAS in EC. KRAS gene mutations have been identified in up to 15–30% of endometrioid ECs. KRAS is a proto-oncogene that, when mutated, acquires a gain-of-function ability, resulting in increased proliferation, transformation, and cell survival [RAS group of proto-oncogenes along with HRAS and NRAS—discussed in more detail in our previous article, along with their effects on mitochondria [KRAS gene encodes the KRAS protein, which is a signal transductor protein with GTPase activity. The function of KRAS is involved in the regulation of cell division and relies on GTP for activation. Activating mutations typically lead to a conformational change in which the protein is locked in its GTP-bound state, resulting in the robust acceleration of the transcription of a wide range of genes [survival . It beloof genes ,261. TheRAS mutations in mitochondria. RAS mutations are known to suppress OXPHOS and enhance glycolysis, mostly via STAT3 activation. In addition, the fission protein Drp1 seems to promote tumor growth in RAS-driven pancreatic cancers, whereas Drp1 loss or inhibition impairs mitochondrial metabolism and tumorigenesis [RAS-driven tumor model [igenesis ,263,264.or model .Based on the above, inhibiting the metabolic advantage in RAS-driven tumors may improve treatment success, as seen with the use of sotorasib, a KRAS inhibitor that is currently approved for KRAS-mutated non-small-cell lung cancers . In addiRAS-related changes summarized in See the CTNNB1 gene. The CTNNB1 gene encodes for the β-catenin protein, which is a multifunctional protein and the effector of the Wingless/int1 (Wnt) signaling pathway. Besides this well-documented Wnt/β-catenin pathway, also called the canonical pathway, Wnt has alternative downstream pathways documented in the literature. Although these noncanonical, β-catenin-independent pathways can be associated with carcinogenesis in many cases, here, we only discuss them briefly. In different cancers, the noncanonical pathway includes the activation of various pathways, such as the PCP/Rho/Jun-N-terminal kinase (JUN), receptor tyrosine kinase (RTK) , or Ca2+ signaling cascades activated via the Frizzled ((Fz), as in the canonical pathway), ROR1/ROR2, or RYK receptors. These noncanonical pathways are described in more detail in [etail in ,268.The β-catenin signaling (Wnt) pathway. This is a fairly complex pathway due to the number of participating proteins. Stated simply, β-catenin, when localized in the nucleus, regulates the transcription of many genes, and an increased amount of nuclear β-catenin is present when Wnt is attached to its receptor. This is the so-called “Wnt ON” state. On the other hand, when Wnt is not attached to its receptor, the lack of downstream pathway activation allows β-catenin to be phosphorylated, leading to ubiquitin-mediated proteolysis in the proteosomes. This is the “Wnt OFF” state. Further details on the participating proteins are as follows:“Wnt ON”: Wnt binds to its membrane receptor  → this induces the cytoplasmic disheveled (DVL) protein, recruited by the Fz receptor → cytoplasmic LRP5/6 protein phosphorylation and Axin protein recruitment → no β-catenin phosphorylation by Axin → no β-catenin degradation → β-catenin accumulates in the nucleus and displaces Groucho/TLE from the TCF-TLE complex, allowing TCF to activate Wnt-responsive genes.“Wnt OFF”: Absent Wnt → no receptor binding and activation → cytoplasmic β-catenin forms a complex with Axin, GSK3, and CK1→ β-catenin phosphorylation by Axin and GSK3 → E3 ubiquitin ligase β-Trcp recognizes phosphorylated β-catenin → β-catenin proteasomal degradation → TCF-TLE complex and histone deacetylases (HDACs) repress Wnt target genes ,270,271.Wnt target genes and their role in carcinogenesis. Wnt target genes include MYC (encoding c-Myc), CCND1 (encoding cyclin D1), and CDKN1A (encoding cyclin-dependent kinase inhibitor p21), among many others. From these genes only, however, it is easy to understand its oncogenic potential. In addition to its effects on cellular proliferation and vasculogenesis, it also regulates cellular development and differentiation, migration, invasion, and general cellular homeostasis [eostasis ,272,273.Wnt signaling pathway and mitochondria. Wnt signaling enhances anaerobic glycolysis in colon cancer cells via increased pyruvate dehydrogenase kinase 1 (PDK1) expression [MYC and PI3K/Akt/HIF-1α activation [pression ,273,274.pression . Additiotivation . PI3K/Aktivation . In additivation ,278. OXPtivation ,279. As CTNNB1-mutated HCC dataset and an in vivo hepatocellular carcinoma model showed that the upregulation of the Wnt/β-catenin pathway significantly increases fatty acid oxidation [A previous study using a human xidation . Furtherxidation .The Wnt/β-catenin pathway also regulates mitochondrial dynamics. In hepatocellular cancer cell lines, the inhibition of the Drp1 mitochondrial fission protein leads to mitochondrial dysfunction, energy depletion, and apoptosis induction via Wnt/β-catenin pathway inhibition , highligWnt/β-catenin pathway and cancer. As previously mentioned, the Wnt/β-catenin pathway plays an important role in cell fate. In many tumors, the activated Wnt/β-catenin pathway induces apoptosis; however, under specific circumstances, it can induce p53-driven apoptosis. For more details on this topic, see the review article by Trejo-Solis and co-workers (2021) [s (2021) .CTNNB1 gene often lead to a mutated form of β-catenin that is resistant to degradation. The intranuclear β-catenin level is subsequently increased with enhanced gene transcription activity [CTNNB1 genes have been linked to several cancers, including EC (~16–71%) and OC , among others [CTNNB1 mutations have been associated with lower-grade (grades 1–2) disease and early-stage (stages I-II) disease, but also with worse recurrence-free survival [Activating mutations of the activity . Alteredg others ,284,285.g others ,315,316.survival .Numerous Wnt/β-catenin-targeting drugs have been researched ,271,287,CTNNB1-related changes summarized in See the FGFR genes and their functions. The FGFR genes (1–4) encode fibroblast growth receptor proteins , which are membrane receptors for fibroblast growth factors (FGFs). The FGF family comprises 22 proteins, which are classified into seven subfamilies, with all subfamily members being structurally related , whereas the FGF11 subfamily members act intracellularly, and the FGF19 subfamily proteins act in an endocrine manner via the αKlotho/βKlotho cofactors ,290. Binic cells .The role of FGF/FGFR in signal transduction pathways. The FGF/FGFR system is important in a broad spectrum of cellular functions, including development, metabolism, cell proliferation, apoptosis, cell migration, and angiogenesis. The single-pass transmembrane receptor FGFRs have an intracellular tyrosine kinase domain at the C-terminus [terminus , activatterminus ,299,300,terminus . FGFRL1 terminus .FGFR signaling can be altered by other, noncanonical binding partners, such as adhesion molecules  and extracellular matrix proteins, making this pathway even more complex. In addition, FGFRs are negatively regulated by multiple processes, including endocytosis and negative feedback phosphorylation events ,299,303.In tumor cells, FGFRs can be activated in both a ligand-dependent and a ligand-independent manner . In the FGF and Klotho proteins. Klotho proteins act as tumor suppressors in various cancers [KLOTHO, or its protein product αKlotho, has been shown to exert a tumor suppressor effect in BC and OC, among other tumors [ cancers ,304, inc cancers . In addir tumors ,306,307.The metabolic effects of FGFs, specifically endocrine FGFs, are numerous and include decreased gluconeogenesis, increased glycogen synthesis, increased peripheral insulin sensitivity, increased glucose metabolism, decreased lipogenesis, and increased fatty acid oxidation by FGF19. Among other effects, FGF21 has been shown to induce PGC-1α, mitochondrial energy production, hepatic gluconeogenesis, and ketogenesis . In cardMoreover, Klotho inhibits autophagy, inhibits glycolysis , fatty acid synthesis, and purine metabolism—some specific to cancer cell effects—making it a promising drug target candidate ,312,313.Increased FGF expression in gynecological malignancies. Increased FGF expression via the previously mentioned “corrupted autocrine/paracrine route” has also been investigated in gynecological malignancies. In serous OCs, FGF1 overexpression was shown to correlate with tumor microvessel density and adverse outcomes [FGF/FGFR SNPs, however, were associated with a reduced risk of OCs, favorable treatment responses, or longer survival [outcomes . A worseoutcomes . Severalsurvival . In addisurvival , highligFGFR alterations have been described in many tumors, with the following tumors showing the highest percentages: urothelial cancer (32%), BC (7–23%), EC , squamous lung cancers (∼13–60%), and OC (∼9%) [FGFR2 alterations are generally associated with a poor outcome [OC (∼9%) ,319,320. outcome .KLOTHO gene polymorphism of the F allele of F352 V was found to be protective against BC and OC susceptibility in a meta-analysis study [Moreover, is study .FGFR alterations include tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or ligand-binding inhibitors, and several of these have been used in clinical studies or are already approved as treatments—with TKI resistance being a concern in FGFR-driven tumors. The mechanism of resistance seems to be via alternatively activated signaling pathways, including PTEN upregulation and others, which are challenging to overcome [FGFR-driven tumors.Targeted treatments of various tumors with overcome ,323,324.overcome ,324. MitSee the summary of FGF/FGFR/Klotho effects in TP53) was discussed in detail along with its relationship with mitochondria in our previous article , and reduced ROS production [TP53 in carcinogenesis. Tumor Protein 53 (tails in ). In shooduction .TP53 increases apoptosis , promotes glycolysis, increases OXPHOS, inhibits the pentose-phosphate pathway, decreases glucose receptor expression, and inhibits fatty acid synthesis. In addition, it blocks the fission protein Drp1, resulting in highly interconnected mitochondria. TP53 also enhances autophagy and reduces ROS production [TP53 in mitochondria. Its mitochondrial effects are summarized as follows: TP53 as a prognostic factor. In general, TP53 mutation is associated with inferior outcomes in many tumors. In EC, p53 immunohistochemistry is a significant prognostic factor, with double-positive estrogen receptor β and p53 associated with an increased incidence of metastasis and/or recurrence .TP53 mutations in OC depends on its grade and histologic type. In high-grade serous tumors, it can be as high as 96%, and it can be as low as 8% in low-grade serous tumors. In addition, in mucinous carcinoma, the frequency is ~57%; in clear-cell OC, it is ~10%; and in endometrioid OC, it is variable (~5–55%) [The frequency of (~5–55%) .TP53-mutant tumors. These include small molecules and compounds subverting the oncogenic activities of mutant p53 into wild-type p53 tumor suppressor functions [TP53-driven tumors include mutant p53 synthetic lethal genes [In addition to conventional chemotherapy, targeted treatments have been a focus of interest in treating unctions ,327. Genunctions . In addial genes ,329. AddTP53 effects in Please also see the Histological subtypes, grading of OCs, and their genetic background. Among all ovarian malignancies, epithelial OC is the most common, accounting for ~90% of ovarian tumors [BRAF, KRAS, and PTEN, with KRAS and BRAF being mutually exclusive [PTEN are more common in endometrioid-type OC. On the other hand, type II tumors are frequently associated with alterations in TP53, BRCA1, and BRCA2.n tumors . In 2004n tumors . Type I xclusive . Of the TP53 alterations have been found in almost 100% of high-grade serous OCs. Other commonly associated gene alterations include BRCA1, BRCA2, NF1, CDK12, Homologous Recombination Repair genes, and alterations in the PI3/Ras/Notch/FoxM1 pathway.High-grade serous OC accounts for ~70–80% of OCs, typically presenting at a late stage and often with disseminated disease . TP53 alKRAS, NRAS, BRAF, ERBB2, and PI3KCA oncogenes [Low-grade serous OC accounts for ~10% of serous OCs. Although they are more indolent compared to high-grade serous ovarian cancer, they are commonly diagnosed at an advanced stage with poor overall survival due to an inadequate response to chemotherapy and hormonal agents ,334. TheARID1A, PIK3CA, PTEN, CTNNB1, and PP2R1A. Microsatellite instability has also been found to result from mismatch repair deficiency [Endometrioid OC accounts for ~10% of epithelial OCs . Genomicficiency ,334. It ficiency .ARID1A, PIK3CA, PTEN, CTNNB1, and PP2R1A genes [ARID1A variants occur in ~50% of clear-cell cases, and PIK3CA variants occur in approximately ~36% [ARID1A mutations [PIK3CA mutation is a possible early event in the transformation of endometriosis into clear-cell OC [PIK3CA mutations were detected in 40% (17/42) of clear-cell OCs, with 71% of these cases also having lost ARID1A expression [PIK3CA transcription through direct interaction with its promoter in ovarian surface epithelial cells [Clear-cell OC accounts for ~5% to 10% of epithelial OCs in the post-menopausal population , with th1A genes . Of the ely ~36% . Clear-cutations . Additio-cell OC . The fre-cell OC ,340,341.pression . Furtheral cells ,344.TERT promoter mutations are seen in ~16% of clear-cell OCs [In addition, FGFR alterations are seen in ∼9% of OCs, whereas cell OCs ,345.The treatment of epithelial OCs is still limited, with often a poor response to conventional chemotherapy, immunotherapy, and surgical resection ,347,348.ARID1A and TERT mutations and their relation to mitochondrial changes. Note that many genes important in the pathogenesis of OCs have already been discussed in previous sections. Additionally, see Here, we further discuss mitochondrial changes in epithelial OCs. In addition, we discuss Mitochondrial changes, as in other types of tumors, are important in the development of OC and in the survival of tumor cells. Although certain gene mutations could also help to identify potential mitochondria-related therapeutic targets in OC (which are discussed separately), there are mitochondrial changes associated with the disease in general.Mitochondrial mass. Increased mitochondrial mass with enhanced mtDNA transcription/translation via increased PGC1α and TFAM and an increased mtDNA copy number have been described in OC cells [OC cells ,349,350.Circulating free mtDNA. The circulating cell-free plasma mtDNA level was found to be increased in epithelial OCs when compared to benign ovarian diseases. However, in this study, it increased with cancer progression but decreased after chemotherapy [otherapy ,352,353.otherapy .mtDNA mutations in OCs. As for mtDNA mutations, mutations in both the D-loop and coding regions have been associated with OC risk and/or disease. In addition, nuclear DNA-coded mitochondrial biogenesis genes and other mitochondrial protein-coding genes have also been found to be altered in OC, many contributing to chemotherapy resistance. For a detailed review see [view see .Changes in mitochondrial metabolism in OCs. Metabolic changes are vital in the pathogenesis, progression, and therapy resistance of epithelial OCs [lial OCs , providilial OCs ,356,357.lial OCs . Anaeroblial OCs . These rlial OCs . Additiolial OCs ,358,359.lial OCs ,360.Abnormal fatty acid synthesis and its enhanced metabolism are also hallmarks of OC cells, with higher fatty acid synthase expression correlated with decreased survival rates ,361. ThiChanges in mitochondrial dynamics in OCs. Mitochondrial dynamics is also altered in OC. Previous data show an increased mitochondrial fission tendency and/or increased Drp1 fission protein or mRNA expression in various OC models [DNML1 gene amplification events amongst all the cancers represented—although only present in ~8% of samples. Furthermore, ~11% of high-grade serous OCs showed increased Drp1 mRNA expression [DNML1, has been linked to poorer survival and chemoresistance in OC [C models . In addipression . The incce in OC . In linece in OC . On the ce in OC . Additioce in OC ,368. Impce in OC ,370.The role of ARID1A in carcinogenesis. ARID1A (AT-Rich Interaction Domain 1A) is a bona fide tumor suppressor gene, given its loss of function in many different tumors. Under specific circumstances, however, it acts as a proto-oncogene (more on this later in this section) [section) .ARID1A gene encodes the ARID1A protein, which is a line-restricted (cell-line-specific) member of the BRG1-associated factor (BAF) complex—the human equivalent of the SWItch Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex, which is responsible for ATP-dependent chromatin remodeling, ubiquitously expressed in all cell types [The ll types ,374,375.ll types ,376. In ll types . Mammalill types . The prell types .The BAF complex has to include one of two mutually exclusive catalytic ATP-ase subunits, both showing helicase activities: SMARCA2/BRM or SMARCA4/BRG1; the latter is found, for example, in embryonic stem cells. In addition to these, there is a set of widely expressed core units  and several different line-restricted subunits  that make up the specific BAF complexes ,374,378.AIRD1A-inactivating mutations [ARID1A, resulting in reduced protein expression and a more aggressive cancer phenotype [ARID1A promoter hypermethylation, but it also can be due to inactivating mutations or in-frame insertions/deletions [Different subunits are associated with different tumors: for example, SMARC1 loss is seen in atypical teratoid/rhabdoid tumors (ATRTs), among others ,381, wheutations ,384,385.utations . Additiohenotype . In varieletions ,386. In eletions ,388,389.BAF complexes, upon nucleosome engagement, undergo conformational changes, resulting in bilateral nucleosome interactions—both at the ATP-ase end and at the other end, such as via the SMARCB1 complex. This unique DNA binding makes these complexes very efficient in DNA remodeling, and specific to these complexes, they may even eject nucleosomes . ARID doBAF complexes and their influences on other signal transduction pathways. Because of its large scale of regulatory effects, BAF complexes alter various downstream cellular pathways, including the sonic hedgehog (SHH) pathway, the Wnt/β-catenin pathway, the E2F/CCND1/Rb pathway, the EZH2/polycomb complex pathway, and the ROCR1/RHOA pathway, and they can also alter nuclear receptor signaling (such as hormone receptors) and can directly interact with proteins, such as p53 [h as p53 ,387. Each as p53 .ARID1A inactivation resulting in tumor initiation in PTEN- or PIK3CA-mutant cells in gynecological malignancies and hypermutated/MSI-type cells in colon cancer [AIRD1A inactivation was insufficient to be the sole driver mutation for tumorigenesis, with rare studies linking ARID1A loss to slower tumor initiation [ARID1A per se is involved in regulating various cellular functions, such as cellular differentiation, the cell cycle, cell migration, DNA repair, angiogenesis, and cellular metabolism ,383,388.itiation ,383,390.ARID1A and BAF complexes in cellular metabolism and mitochondria. The effects of the BAF complex and ARID1A on cellular metabolism and mitochondria are numerous. In a recent in vitro OC study, Zhang and co-workers showed that ARID1A loss resulted in increased mitochondrial membrane potential, increased mitochondrial mass, and enhanced mitochondrial fission, likely at least in part due to increased c-Myc expression [pression .ARID1A- and SMARCA4-mutant tumors were found to be more sensitive to the inhibition of OXPHOS when compared with wild-type controls in a lung cancer study [ARID1A-mutated clear-cell OC [er study ,392. In -cell OC . In addi-cell OC .EZH2, histone modifications (HDACs);SHH ;p16 and p21, CDK4/5, Rb, and E2F4 ;Wnt/β-catenin ;TP53, p53 ;TERT ;Transforming growth factor β (TGFβ) ;MYC ;KRAS ;PI3K/AKT/mTOR .Furthermore, ARIDA1 affects several downstream pathways, such as ,395,396:In addition to these, functional ARID1A has an important role in DNA damage repair . It alsoAltering various mitochondrial functions therefore could be beneficial in tumors with ARID1A loss . See Epigenetic modulations, such as DNA methylation or histone modifications, are discussed in detail in our previous article  [EZH2. In short, enhancer of zeste homolog 2 (EZH2) is an epigenetic modulator and is part of the polycomb repressive complex 2 (PRC2). PRC2 is a key gene transcription inhibitor acting via the trimethylation of lysine 27 of histone H3 (H3K27). EZH2 can be induced at the transcriptional level or by post-transcriptional modifications. When EZH is inhibited or knocked down, reduced glycolysis, enhanced OXPHOS, and reduced fatty acid synthesis are seen in vitro, along with apoptosis inhibition. Its effect on mitochondrial dynamics, however, has not been elucidated ,373.With the loss of ARID1A, inhibition via EZH2 is lost, subsequently increasing H2K27 methylation and making the transcription sites less accessible . In precHDAC6, along with AURKA and TERT [ARID1A-mutant tumors. Moreover, HDAC6 inhibition improved animal survival in a clear-cell OC model when given with an anti-PD-L1 immune checkpoint inhibitor [Histone deacetylases (HDACs). Histone deacetylases (HDACs) remove acetyl groups from histones, resulting in a more closed chromatin structure and thus interfering with gene transcription. HDAC enzymes were found to be overexpressed in various malignancies, such as those with ARID1A loss ,390. As and TERT . HDAC6 hand TERT ). In addnhibitor . In addinhibitor ,401. HDAnhibitor .HDAC1/2 inhibition resulted in c-Myc-dependent glycolysis inhibition, enhanced OXPHOS, fatty acid oxidation, and mitochondrial biogenesis in a GBM model . In addiSee also The sonic hedgehog (SHH) pathway functions to regulate cell homeostasis, differentiation, proliferation, and vasculogenesis. The SHH protein is part of the hedgehog protein family, comprising two other ligands (Indian hedgehog/IHH and Desert hedgehog/DHH) besides SHH, named after their activating ligands ,407,408.In the canonical pathway, the SHH protein binds to one of the cell membrane receptors, Patched 1 (PTCH1). After SHH binding, PTCH1 becomes inactivated and can no longer inhibit the SMO (Smoothened) protein, which then translocates to the plasma membrane from the cytoplasm and frees the glioma-associated oncogene homolog (GLI) zinc finger transcription factors . GLIs subsequently translocate to the nucleus, where they activate their target genes. In the absence of the ligand, PTCH1 inhibits SMO, which then remains in the cytoplasm, where it eventually degrades. As a result of this, GLI target genes are not activated ,407,408.The noncanonical SHH pathway, on the other hand, can be classified into three types: (1) PTCG-mediated, (2) SMO-dependent/GLI-independent, and (3) SMO-independent GLI activation. These, however, include any SHH effect that is not the canonical pathway, including downstream metabolic effects and mitochondrial changes.HH pathway and cellular metabolism. The activation of the HH pathway has a significant effect on glucose metabolism. Mouse cell line studies showed that both active and inhibited SHH/SMO signaling can induce the “Warburg effect”, with the latter occurring via the AMPK pathway [ pathway . In addi pathway . On the  pathway . In adul pathway .Furthermore, active SHH signaling was shown to decrease mitochondrial fission via Drp1 inhibition in an endometrial hyperplasia model .During neuronal development, the npBAF complex suppresses the SHH pathway . In addiThe effects of ARID1A loss on the SHH pathway are summarized in INK4a), encoded by the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, is a tumor suppressor, inhibiting cyclin-dependent kinases (CDK4/6) that maintain Rb in a phosphorylated state when bound to cyclin D1 (encoded by CCND1) [The p16 protein  ,414,415.y CCND1) ,414,415.y CCND1) , recent y CCND1) ,414,417.These changes were studied in an in vitro model, which showed that p16-deficient cells have a higher mitochondrial mass with the increased expression of the mitochondrial transcription of PGC-1-related coactivator (PRC) and transcription factor A (TFAM), the increased expression of mitochondrial respiratory subunit proteins, and, paradoxically, decreased respiratory capacity. These subsequently resulted in enhanced mitochondrial ROS generation, which can promote cellular migration . MoreoveARID1A knockdown leads to decreased CDKN2A expression with subsequently increased cell proliferation in a KRAS-mutant pancreatic cancer cell line [A previous study showed that ell line . In addiell line .CCND1 transcription inhibition can be due to the direct recruitment of HDACs to the CCND1 promoter region by a functional BAF complex/SMARCB1 and likely ARID1A [CCND1 transcription then results in decreased cyclin D1 expression, resulting in cellular senescence. On the contrary, BAF/SMARCB1 inactivation results in increased cell proliferation [Additionally, cyclin D-CDK4 expression is associated with increased mitochondrial biogenesis, whereas CDK4 inhibition has the opposite effect in Drosophila . Among oy ARID1A ,414,415.feration ,414,415.Furthermore, ARID1A loss reportedly increases p21 expression, resulting in increased angiogenesis. Besides its effect on angiogenesis, p21 is also important in cell cycle progression and has been reported to increase the mitochondrial mass (without increased OXPHOS) .The effects of ARID1A loss on p16, p21, and cyclin D1 are summarized in ARID1A loss results in the activation of the Wnt/β-catenin pathway . Its effTP53 expression and also directly binds to the p53 protein. ARID1A loss therefore results in inhibited TP53 expression/p53 effect [TP53, see ARID1A enhances 3 effect ,422. ForTERT transcription by directly binding to its promoter region and via histone modification [TERT, see ARID1A negatively regulates fication ,395. ForARID1A loss results in the activation of the RAS pathway . For morSee these effects also in ARID1A loss results in TGF-β inhibition, leading to increased cell proliferation ,396. TGFMYC activation [MYC discussed in detail in our previous manuscript [MYC, is a transcription factor that alters the expression of a large number of genes. Similarly to RAS, MYC activates TP53, enhances ROS production, and causes replication stress. Furthermore, MYC increases glycolysis, the expression of glucose transporters (GLUT1 and GLUT3), lactate transporters, and glutamine transporters but suppresses OXPHOS. In addition, MYC increases β-oxidation and glutaminolysis. It also promotes Drp1-dependent fission and increases mitochondrial biogenesis . Mitochondrial trafficking is also induced by MYC via RHOT1, RHOT2, TRAK2, and Kif5B [ARID1A loss results in tivation , with thARID1A loss results in the activation of the PI3K/AKT/mTOR pathway . For morTERT gene), and a telomerase RNA component (TERC) that is known for its function in telomere elongation [TERT gene and TERT promoter alterations  are fre such as .TERT functions. In addition to its telomere elongation effect, TERT also has so-called noncanonical functions. These include the regulation of chromatin structure, the protection of mtDNA, RNA silencing, epigenetic changes, the subsequent activation of signaling pathways (such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or Wnt/β-catenin signaling pathways), mitochondrial and metabolic regulation, and an increase in cell adhesion and migration [igration .TERT in mitochondria. Although the relationship between mitochondria and TERT is not fully understood, several interactions have been documented, including apoptosis regulation, the protection of mtDNA from oxidative stress, the regulation of glucose metabolism and uptake, mitochondrial dynamics, and autophagy. TERT, although primarily localized in the nucleus, can be shuttled to the mitochondria, but it may also reside in the cytoplasm [ytoplasm . Intramiytoplasm  followinytoplasm . One stuytoplasm . Additioytoplasm . In one ytoplasm . Additioytoplasm .An in vitro BC study showed that transfection with a TERT-promoter construct resulted in enlarged stem-cell-like cells that showed increased mitochondrial biogenesis and functional activity and increased expression of glycolytic enzymes . A metabTERT and telomerase function. The prevalence of upregulated TERT expression and thus telomerase activity in cancers, as well as tumor cell dependence on telomerase function for perpetual replication, makes telomerase a valuable target for cancer therapy. Current therapeutic strategies for targeting telomerase include immunotherapies, direct small-molecule inhibitors, altered TERT gene expression, and the indirect disruption of telomerase regulation [TERT-altered tumors, therefore, might be beneficial.gulation . A possigulation . This maTP53-altered tumors, with reduced OXPHOS also described in type I ECs, likely contributing to their less aggressive nature , is highly expressed in both BC and estrogen-driven ECs, increasing their hypoxia tolerance. COX7RP works as a promoting factor for mitochondrial respiratory supercomplex assembly, leading to efficient OXPHOS. COX7RP overexpression, associated with an inferior prognosis in BC patients, promoted EC growth in an in vivo model and alters the metabolic profile of cancer cells. It largely affects glucose homeostasis and regulates the expression of TCA intermediates [Another common participant in the pathogenesis of type I ECs, OCs, and BC is estrogen. Interestingly, previous reports described its direct mtDNA binding via the ERα and ERβ receptors . In addimediates .Are mitochondrial-targeted therapies going to be used in BC, EC, or OC? Based on the evidence that, in many cases, therapy-resistant tumors have significant, targetable metabolic and/or mitochondrial changes, it is definitely promising. In addition, several drugs were shown to be useful in preclinical and/or clinical settings—some of them in other cancer types. Having information on the genetic changes in a tumor sample may help to individualize metabolic targeting.


Cupriavidus necator C39 (C. necator C39) was isolated from a Gold-Copper mine in Zijin, Fujian, China. C. necator C39 was able to tolerate intermediate concentrations of heavy metal(loid)s in Tris Minimal (TMM) Medium (Cu(II) 2 mM, Zn(II) 2 mM, Ni(II) 0.2 mM, Au(III) 70 μM and As(III) 2.5 mM). In addition, high resistance to multiple antibiotics was experimentally observed. Moreover, strain C39 was able to grow on TMM medium containing aromatic compounds such as benzoate, phenol, indole, p-hydroxybenzoic acid or phloroglucinol anhydrous as the sole carbon sources. The complete genome of this strain revealed 2 circular chromosomes and 1 plasmid, and showed the closest type strain is C. necator N-1T based on Genome BLAST Distance Phylogeny. The arsenic-resistance (ars) cluster GST-arsR-arsICBR-yciI and a scattered gene encoding the putative arsenite efflux pump ArsB were identified on the genome of strain C39, which thereby may provide the bacterium a robust capability for arsenic resistance. Genes encoding multidrug resistance efflux pump may confer high antibiotic resistance to strain C39. Key genes encoding functions in degradation pathways of benzene compounds, including benzoate, phenol, benzamide, catechol, 3- or 4-fluorobenzoate, 3- or 4-hydroxybenzoate and 3,4-dihydroxybenzoate, indicated its potential for degrading those benzene compounds.Here a multiple heavy metal and antibiotic resistant bacterium  Cupriavidus is a genus of the family Burkholderiaceae, members of this genus are well known for their heavy-metal resistance and diverse metabolic capabilities in different niches, especially from heavy metal and organic-chemical contaminated soils, such as halobenzoates, chlorophenols and nitrophenols, and thus making them useful for bioremediation  synthesis, which is a representative member of biodegradable polyesters, were not identified on the genome of C. necator strain C39 [In addition, the metabolic pathway for aromatic compound degradation was reconstructed using the KEGG database. Pathway analysis suggested that strain C39 should be able to completely degrade benzoate, benzamide, catechol, 3- or 4-fluorobenzoate, 3- or 4-hydroxybenzoate, 3,4-dihydroxybenzoate and phenol . Compareegrading . Key genrain C39 .C. necator strain C39 and C. metallidurans strain CH34 in different categories. Under the category “Metabolism of aromatic compounds”, strain C39 has 10 unique roles which belong to benzoate degradation, biphenyl degradation, aromatic amine catabolism, gentisate degradation and other subsystems respectively. This, at the genetic level, explains why strain C39 had a strong ability to degrade benzoate in previous experiments. Under the category “virulence, disease and defense”, the common genes of the two can be subdivided into 39 roles, and the unique genes of strain C39 only have 3 roles, while strain CH34 has 12 roles. Strain CH34 has more genes related to copper homeostasis and cobalt, zinc and cadmium resistance than strain C39, which can also be used to explain why its MIC results are higher than strain C39. At the same time, we speculate that although strain C39 also has many RNDs, these RNDs may not all play the role of drug resistance and cannot be used for heavy metal efflux, so its MIC results are lower than strain CH34.The function-based comparison of RAST was used to compare the similar and different genes between Cupriavidus necator C39, isolated from a gold-copper mine. Interestingly, strain C39 has shown significant resistance to some metals and antibiotics and also the potential to degrade aromatic compounds such as benzoate, phenol, indole, p-hydroxybenzoic acid or phloroglucinol anhydrous. The whole genome analysis of strain C39 revealed multiple genes predicted to encode functions responsible for metal and antibiotic resistance and the degradation pathway of aromatic compounds. Among these genes, the arsenic-resistance (ars) cluster GST-arsR-arsICBR-yciI and a scattered gene encoding ArsB is predicted to confer arsenic resistance; genes encoding multidrug resistance efflux pump are predicted to confer high antibiotic resistance to strain C39. Moreover, the presence of a number of genes predicted to encode key enzymes in the degradation pathway of benzene compounds indicate the verified potential of strain C39 to degrade these compounds. Our study displays the presence of multiple heavy metals and antibiotic-resistance determinants


Dacryodes Vahl. species, belonging to the Burseraceae family, are widely used in traditional medicine in tropical regions to treat a range of ailments including malaria, wounds, tonsillitis, and ringworms. This review discusses the distribution, ethnobotanical uses, phytochemistry, and bioactivities of Dacryodes species. The intent is to spur future research into isolating and identifying key active principles, secondary metabolites, and crude extracts, and evaluating their pharmacological and toxicological effects, as well as the mechanism of actions to understand their medicinal benefits. A systematic review of scientific electronic databases from 1963 to 2022 including Scifinder, Scopus, Pubmed, Springer Link, ResearchGate, Ethnobotany Research and Applications, Google Scholar, and ScienceDirect was conducted with a focus on Dacryodes edulis (G.Don) H.J. Lam and Dacryodes rostrata (Blume) H.J. Lam. Pharmacological data revealed that D. edulis isolates contain secondary metabolites and other phytochemical groups belonging to the terpenoids class with anti-microbial, anticancer, antidiabetic, antiinflammatory and hepatoprotective activities, highlighting its pharmacological potential in the therapy or management of diverse cancers, cardiovascular, and neurological diseases. Thus, phytochemicals and standardized extracts from D. edulis could offer safer and cost-effective chemopreventive and chemotherapeutic health benefits/regimen, or as alternative therapeutic remedy for several human diseases. Nevertheless, the therapeutic potential of most of the plants in the genus have not been exhaustively explored with regard to phytochemistry and pharmacology, but mostly complementary approaches lacking rigorous, scientific research-based knowledge. Therefore, the therapeutic potentials of the Dacryodes genus remain largely untapped, and comprehensive research is necessary to fully harness their medicinal properties. Plants have been used for a variety of purposes for thousands of years, including medicinal purposes. The use of plants for health and healing can be traced back to ancient civilizations, such as Sumeria, Mesopotamia, Egypt, Greece, and Islam. The oldest written evidence for the use of plants for health dates back to around 5000 years ago and was discovered on a Sumerian clay slab from Nagpur ,2. TradiDacryodes Vahl., a genus belonging to the family Burseraceae, comprises around 40 species of trees and shrubs that are naturally found in tropical areas of Africa and the Americas. The African pear or “Safou”, scientifically known as Dacryodes edulis (G.Don) H.J. Lam, is the most popular species in this genus . Eq. EqDacryCameroon . In CameCameroon . In Nigeas “ube” . It is aas “ube” ,70,71. D forests , and D. l Guinea .Dacryodes rostrata is widely found in Malaysia, more precisely in the region of Sabah, Sarawak anthracene  [D. rostrata peels on breast cancer cell lines was determined using the MTT method. The results showed that the peel water extract had a moderate cytotoxic effect on T-47D breast cancer cells  [The extract from d vagina . There hd vagina . Mvondo g/kg BW) . In vitrctively) .D. edulis has been shown to be effective in managing diabetes in Alloxan-induced diabetic rats. Sub-toxic doses of the hexane extract (400 to 1600 mg/kg) administered orally resulted in a significant decrease in overall cholesterol, triglycerides, hyperglycaemia, ALT, LDL-C, and ALP levels [D. edulis leaf extract demonstrated significant α-amylase and α-glucosidase inhibitory activity in vitro. In streptozotocin-induced diabetic Albino Wistar rats, the crude extract, H2O-MeOH, and EtOAc fractions significantly decreased fasting blood glucose levels from 463 to 174 mg/dL, 427.8 to 151 mg/dL, and 460 to 120.5 mg/dL, respectively, revealing the anti-hypoglycemic potential of D. edulis leaves, respectively, in streptozotocin-induced diabetic Albino Wistar rat model, revealing the anti-hypoglycaemia potential of D. edulis leaves [D. edulis leaves had a significant effect on type 2 diabetes induced by fructose-streptozotocin in rats compared to the standard drug metformin. This illustrated the ability of this fraction to decrease the level of glucose in the blood, improve β-cell dysfunction, serum insulin, inhibit insulin resistance, and improve weight and morphology of the pancreas [The fruit extract of P levels . Additios leaves . Furtherpancreas .Dacryodes edulis methanol extract of leaves was prepared, then H2O-MeOH, EtOAc, and hexane fractions were prepared for antioxidant assays. As a result, H2O-MeOH and EtOAc fractions exhibited pronounced radical scavenging and reductive activity in vitro. Additionally, further in vivo tests showed the capacity of the crude extract and the resulting fractions to reduce the oxidative stress burden in diabetic rats [D. edulis ethanol extract promotes the restorative activity in oxidative stress CCl4-induced rats and in tissue (blood and liver) damage [Dacryodes edulis aqueous extract of seeds was assayed for its antioxidant potential by Ogunmoyole et al., and it was found that the extract obtained at 100 °C had better activity than the extract obtained at room temperature with 65% and 40% of free DPPH free radicals scavenged, respectively. The similar results were obtained with FRAP method where the boiled extract reduced more than 75% of Fe3+ comparatively to 35% of unboiled extract [D. edulis seed was evaluated for its antioxidant activity, scavenging, 37% of free radicals relative to vitamin C (100%) and β-tocopherol (98%). It also exhibited significant concentration-dependent AChE inhibitory activity [D. edulis during the maturation from 4 weeks after anthesis to mature fruits (20 weeks) following three methods namely: H2O2, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-, and malondialdehyde (MDA) assays. This resulted in the CHCl3 /methanol (1:2) extract scavenging 45.47, 45.1 and 18.3% of radicals in the three methods, respectively, and the activities were higher with mature fruit [50 = 0.223 mg/mL) compared to vitamin C , quercetin  and butylate hydroxyanisol  [tic rats . Nguefac) damage . Dacryod extract . These ractivity . Furtherre fruit . Jolayemre fruit . The fla8 mg/mL) .50 values obtained, it is evident that the antioxidant activity of D. edulis is directly linked to its flavonoid content. Additionally, the flavonoid content in D. edulis fruits can be explored for potential therapeutic applications. The ex vivo anti-oxidative activity of D. edulis extract was tested on pancreas and liver tissues collected from male albino rats. These organs were first injured with FeSO4, and untreated injured hepatic tissue exhibited an increase in glucose-6-phosphatase activity, indicating an increase in glycogenolysis and gluconeogenesis. The important (p < 0.05) reduction in this activity, due to the use of the aforementioned extract, highlights their antihyperglycemic potential with an increase in glycogenesis [D. edulis ethanol extract was more productive  than the aqueous extract (44.57 µg/mL) l-ascorbic acid (8.27 µg/mL) using the DPPH method; even though the activity of the ethyl acetate fraction was the smallest, this fraction was more effective in vivo on the activities of several enzymes such as GSH, SOD, and Alpha glucosidase [D. edulis as an antioxidant depends on various factors, including the solvent used, extraction temperature, and assay method (in vivo or in vitro). Nevertheless, these results suggest that therapeutic investigations should prioritize the flavonoid content, the ethanolic and ethyl acetate extracts, high-temperature extraction, and in vivo assays. For traditional purposes, people should use an alcoholic solvent like palm wine to enhance its activity in treating diseases associated with free radicals.Based on the previous ICogenesis . The in cosidase . OverallD. rostrata were assayed for their antioxidant activities. The seeds exhibited higher activities than peels followed by pulps, and this was following the phenolic contents of these parts [2O, n-BuOH, and EtOAc), yielding similar results for each part of the fruits. A recent report on the antioxidant potential of H2O-EtOH (50%) extract of the peels of D. rostrata showed that they exhibited an activity with IC50 values of 59.27 ppm and 121.7 ppm in the 2,2-diphenyl-1-picrylhydrazyl assay, which is classified as strong and moderate activity, respectively [2O-EtOH (50%) extract of these fruits, stating that the crude extract of each part had higher activity than any of the fractions [D. rostrata support the findings previously suggested for D. edulis concerning the use of alcoholic solvents.The defatted 50% ethanol extracts of each part of se parts . The ethse parts . Furtherectively . Thavamoractions . These rDacryodes edulis seed’s ethanol extract was reported to have an hepatoprotective effect. Albino rats of the Wistar strain were treated with the seed extract for two weeks and then CCl4 on the fourteenth day, showing no liver damage, whereas rats that were only subjected to CCl4 showed liver damage [4-induced hepatotoxicity, treated with ethanol extract of D. edulis seeds, highlighted the potential of this extract to restore hepatocyte functions [D. edulis was evaluated during their maturation from four weeks after anthesis to mature fruits on male Wister rats. The CHCl3/methanol (1:2) oil extract used to feed rats showed activity in increasing order from immature fruits to mature ones [r damage . Similarr damage . The livunctions . Furtherure ones , thus inD. edulis leaf was previously evaluated on male Wistar rats. After 24 h, no damage was observed on their livers and kidneys, thereby indicating the safety of the leaf extract [D. edulis methanolic leaf extract decreased erythrocytic indices at high doses indicating anemic potentials; however, liver and kidney function indices were similar to control levels [The toxicity of ethyl acetate and the aqueous fractions of  extract . Tene et extract . In a reDacryodes species provide evidence for their traditional use in treating various ailments. Additionally, other species in the genus should be investigated for their potential therapeutic benefits. Most of the reported assays have employed outdated antioxidant test methods, and hence, modern techniques are required to better comprehend the biological activities of these species. Furthermore, future in vitro and in vivo studies should focus on the activities of isolated flavonoids, as well as phytochemicals belonging to other classes of compounds, or to be isolated. To sum up, these findings on the biological properties of D. edulis have been consumed in rural communities throughout the tropical regions. Different species of the Dacryodes genus have bioactive compounds, such as saponins, terpenoids, flavonoids, tannins, reducing sugars, and alkaloids, justifying their uses in ethnomedicine. The tree was screened quantitatively and qualitatively to identify the phytochemical elements accountable for the ethnomedicinal properties [1–14 identified as α-Thujene (1), α−Pinene (2), Camphene (3), Sabinene (4), β-Pinene (5), α−Phellandrene (6), α-Terpinene (7), p- Cymene (8), 1,8-Cineole (9), γ−Terpinene (10), cis Sabinene hydrate (11), trans Sabinene hydrate (12), Terpinen-4-ol (13) and α−Terpineol (14) were reported from the essential oil of the D. edulis resin [15–19 i.e., Methyl gallate (15) [16) [17) [O-α-l-rhamnoside (18) [19) [D. edulis [20) and Sitosterol-3-O-β-d-glucopyranoside sterol (21) were from the stem bark of D. edulis [22) was isolated from the seeds of D. edulis [23–25 i.e., Vanillic acid (23) [24) [25) [D. edulis. From the same species, the following compounds: Kaur-15-ene (26) [27) [28) [29) [30) [31) [trans Phytol (32) [33) [34) [35) [36) [37) was isolated from the stem bark of D. edulis [D. edulis, as well as their biological activities.Since plant chemical constituents are physiologically active, research into these substances is crucial for finding new drugs and creating novel therapeutics for medical disorders . Over thoperties   , Ellagic15) [16) ,100, Que. edulis . Gallic . edulis ,102 and cid 23) , Vanilli23) [24) , (-)-epi , Vanill24) [25)  were ideene (26) , 9-(4-me26) [27) , Xanthon27) [28) , Octadec28) [29) , Phytol 29) [30) , Ethyl-130) [31) , trans Ptol (32) , Ascorbi32) [33) , Urs-12-33) [34) , 2,3,23-34) [35) , and Sit35) [36)  were ide35) [36)  -epicatechin are among the compounds identified from D. rostrata, which has only been investigated for its antioxidant activities. These findings highlight the potential of the Dacryodes genus as a source of pharmacologically and medicinally important chemicals, making it a promising alternative treatment for various ailments and a starting material for developing new pharmaceutical products.The purpose of this review is to discuss the ethnobotanical uses, distribution, pharmacology, and phytochemistry of Dacryodes species support their use in traditional medicine by rural communities. However, the pharmacological preparations from trees of this genus have unclear prescriptions and mechanisms of action, and their efficacy, as well as related side effects, are not yet fully recorded or understood. Therefore, extensive further research is needed to establish this missing knowledge. Although there has been in vitro research on the biological properties of Dacryodes species, there is limited information on the biological properties of their chemical constituents. More research is required on phytochemistry, pharmacology, and toxicology, as well as in vivo experiments using isolated chemical compounds and crude extracts from the species. Molecular docking investigation, metabolomics, and high-throughput screening could be used to gain further insights into the phytochemicals produced by Dacryodes trees and their associated biological effects.The biological activities discovered in


Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of death worldwide. Efficient non-invasive blood-based biomarkers for CRC early detection and prognosis are urgently needed.To identify novel potential plasma biomarkers, we applied a proximity extension assay (PEA), an antibody-based proteomics strategy to quantify the abundance of plasma proteins in CRC development and cancer-associated inflammation from few μL of plasma sample.Among the 690 quantified proteins, levels of 202 plasma proteins were significantly changed in CRC patients compared to age-and-sex-matched healthy subjects. We identified novel protein changes involved in Th17 activity, oncogenic pathways, and cancer-related inflammation with potential implications in the CRC diagnosis. Moreover, the interferon γ (IFNG), interleukin (IL) 32, and IL17C were identified as associated with the early stages of CRC, whereas lysophosphatidic acid phosphatase type 6 (ACP6), Fms-related tyrosine kinase 4 (FLT4), and MANSC domain-containing protein 1 (MANSC1) were correlated with the late-stages of CRC.Further study to characterize the newly identified plasma protein changes from larger cohorts will facilitate the identification of potential novel diagnostic, prognostic biomarkers for CRC. CRC proCurrently, the most commonly used diagnostic tools for CRC screening and prevention include colonoscopy and flexible sigmoidoscopy, as well as the guaiac-based fecal occult blood test or the immunochemical fecal occult blood test, also known as the fecal immune test . These tAdvances in proteomic-based technologies in the last decade have expanded the number of candidate biomarkers and led to a better comprehension of the CRC progression as well as the identification and characterization of related molecular signatures. The most recent advancement of Proximity Extension Assay (PEA) allows the quantification of over 3,000 proteins from low amounts of a sample by the combination of DNA-conjugated antibodies and next-generation sequencing . ApplicaIt was recently reported that two various multimarker panels consisting of five circulating proteins might be used as an efficient tool for the early and late-stage detection of CRC, including advanced adenomas, or in the prediction of overall survival in Germany and Chinese cohorts , 19. In Both chronic inflammation, such as IBD, and sporadic, cancer-associated inflammation are well-known as key factors in CRC progression and development. Inflammation alters the communication between a variety of cell types, including innate and adaptive immune cells, epithelial cells, and stem cells. These intricate networks of cytokines, growth factors, receptors, and other molecules interaction result in either a tumor-promoting or inhibiting environment . Thus, iThe purpose of our study was to identify the protein expression changes in the plasma of CRC patients compared to healthy controls as well as between the early and late stages of CRC and inflammatory status. Therefore, an inflammation panel including 368 proteins was selected to be detected in this study. We hypothesized that CRC development, tumor stage, and inflammation-caused changes in protein level will be reflected in the circulating blood and as such, we would be able to obtain a panel of biomarkers with potential translation into clinics to improve patient care. In this study, we quantified the plasma protein profiles derived from 38 CRC patients and their age- and sex-matched 38 healthy subjects using the PEA technology and protein panels consisting of 368 oncology- and 368 inflammation-related protein biomarker candidates. We quantified 690 proteins, among which 78 differentially expressed proteins (DEPs), were elevated and 124 DEPs were reduced in patients with CRC. We found protein signatures associated with cytokine interactions, oncogenic signaling pathways, exacerbated apoptosis, as well as metabolism reprogramming. Additionally, we determined protein changes linked to cancer-associated inflammation and novel potential prognostic biomarkers associated with tumor stages. Linear regression model analysis revealed that carbonic anhydrase (CA11), a cluster of differentiation 276 (CD276), colony-stimulating factor 3 (CSF3), and interleukin 12 receptor subunit beta 1 (IL12RB1), were positively associated with inflammatory status, whilst amyloid beta precursor protein binding family B member 1 interacting protein (APBB1IP) and C-X-C motif chemokine ligand 6 (CXCL6) were negatively associated. Moreover, linear regression model analysis of tumor stage indicated high plasma levels of Fms-related tyrosine kinase 4 (FLT4), MANSC domain-containing protein 1 (MANSC1), and lysophosphatidic acid (LPA) phosphatase type 6 (ACP6), that could be used as potential prognostic biomarkers for advanced CRC. In contrast, high levels of interferon γ (IFNG), interleukin (IL)32, and IL17C in early CRC stages indicate that these proteins can discriminate between early and late stages, patients. Validation of these identified plasma protein changes with larger cohorts will facilitate the identification of potential novel diagnostic, prognostic biomarkers for CRC.22.1® K2EDTA tubes during the day of the planned CRC resection, centrifuged, aliquoted plasma and serum, and stored at -80°C until use.The study was retrospective and consisted of 38 patients who underwent CRC surgery  between June 2019 and April 2021 and 38 age- and sex-matched healthy subjects. All CRC patients had a positive colonoscopy and pathology-confirmed malignant neoplasm of the rectum or colon. Among them, 63.2% (24/38) were diagnosed with late-stage CRC (III-IV) according to the Union for International Control TNM classification and 28.9% (11/38) had inflammation according to the pathologist assessment Table 1.2.2® Explore 384-Oncology and -Inflammation panel, Olink Proteomics, Uppsala, Sweden)  2. Brief Sweden) , 20. PEA2.3p-value < 0.05. The built-in R function cor.test was used to calculate the point-biserial correlation between protein expression and tumor stage or inflammation status, the p-value < 0.05 was considered significant. Gene set enrichment analysis with Gene Ontology terms was performed using ClusterProfiler (version 4.6.0), while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis via active subnetworks from STRING database was conducted using “pathfindR” (version 1.6.3), with FDR < 0.05. “ggplot2” (version 3.3.5) was used for graphics generation, excluding heatmaps that were generated using “ComplexHeatmap” (version 2.6.2). The hierarchical clustering (Euclidean distance) was implemented to visualize the patterns of DEPs among samples after the z-score transformation of NPX values; DEPs were split by k-means clustering. T test was used for the calculation of continuous variables (protein levels) by using GraphPad Prism version 9.0 .Almost all statistical analyses were performed in RStudio (version 1.3.1093) using R (version 4.0.3). First, proteins were filtered when the quality control was negative or the calculated NPX values were below the respective protein limit of detection (LOD) in at least 50% of samples from one of the study groups. The remaining NPX values below the LOD were imputed with the respective LOD/√2. Moderated t-test from the R package “limma” (version 3.46.0) was used to test differential protein abundance between CRC patients and healthy subjects. Additional analysis was performed using the general linear model regression approach with analysis of contrasts using the R package “emmeans” (version 1.6.2.1). A general linear model was fitted to the expression of each protein in all CRC patients using tumor stage and inflammation as independent variables, and sex as a confounding factor. The false discovery rate (FDR) was determined using the Benjamini & Hochberg correction. Proteins were considered differentially expressed when FDR adjusted 33.1To determine the changes in the protein profiles in peripheral blood caused by CRC development, we performed plasma protein analysis by using PEA technology. Out of the total 736 proteins from the Inflammation and Oncology Explore panels, after removing repetitions in the panels and after removal of proteins with low detection rates among the samples, 690 proteins were quantified. Among them, 78 proteins were elevated and 124 were reduced in the 38 CRC patients compared with their age- and sex-matched healthy controls , 23–28, via active subnetworks was performed. Plasma protein changes were mainly associated with the cytokine-cytokine receptor interaction, including high plasma level of T-cell chemoattracting chemokine CXCL9 and the immune cell chemoattractant CCL23, as well as several signaling pathways including mitogen-activated protein kinase (MAPK), resistance to audiogenic seizures (Ras), tumor necrosis factor (TNF), nuclear factor kappa B (NF-κB), and IL17 signaling pathways . Correlation analysis revealed 56 proteins significantly correlated with inflammation, among which 7 proteins, CA11, CD276, CSF3, IL3RA, IL12RB1, MILR1, and SEMA4C were positively correlated, while 46 proteins including ACP6, APBB1IP, CXCL6, and dicarbonyl and L-xylulose reductase (DCXR) were correlated negatively -signal transducer and activator of transcription (STAT) signaling pathways, as well as pentose and glucuronate conversion  and late (III and IV) stages of CRC. The correlation analysis showed that 13 proteins, ACP6, CCL23, C-type lectin domain family 4 member G (CLEC4G), FLT4, IL1R2, IL6, MANSC1, marginal zone B and B1 cell-specific protein (MZB1), S100 calcium-binding protein A12 (S100A12), secretoglobin family 1A member 1 (SCGB1A1), SPARC-related modular calcium-binding protein 2 (SMOC2), thioredoxin domain containing 15 (TXNDC15), and WAP, follistatin/kazal, immunoglobulin, kunitz and netrin domain containing 2 (WFIKKN2) were positively correlated with tumor stage, whereas 7 proteins, including IFNG, IL32, integrin subunit alpha 11 (ITGA11), ITGAV, selectin P ligand (SELPLG), trefoil factor 2 (TFF2), and transmembrane serine protease 15 (TMPRSS15) were correlated negatively , which have not been previously reported as plasma diagnostic biomarkers. The protein expression of DPEP2, a dipeptidase involved in leukotriene metabolism, was recently found as a modulator of macrophage inflammatory responses, protecting mice against Coxsackievirus B3-induced viral myocarditis . InteresRSPO2 and RSPO3 was presented by 4-10% of colon subjects  cells, and immune regulators . The patients/participants provided their written informed consent to participate in this study.Conceptualization, ZC; methodology, VU-S; formal analysis, VU-S; resources, KD-C, NF, AP, JPD, MZ, EŚ, ŁS, MJ, DB, WZ, TN, WM, AAd, AAm, MP, AH-L, JR, and ZC; data curation, AJ, QH, and NF; writing—original draft preparation, AJ; writing—review and editing, DM VU-S, AJ, AP, JD, and ZC; visualization, VU-S; supervision, BL and ZC; project administration, NF, AJ, and ZC; funding acquisition, AP, JPD, and ZC. All authors contributed to the article and approved the submitted version.