Molecular mechanisms in endometriosis: linking JAK/STAT pathway, ferroptosis, and microbial dysbiosis

Endometriosis is a chronic gynaecological disorder characterized by ectopic endometrial growth, inflammation, pain, and infertility. Current therapies, largely hormonal and surgical, have limited efficacy and compromise fertility, underscoring the need for alternative approaches that directly address the inflammatory drivers. Recent evidence suggests that gut microbiota dysbiosis and iron overload contribute to the pathophysiology of endometriosis, with excess iron potentially inducing ferroptosis, a regulated form of lipid peroxidation-driven cell death that amplifies inflammation. Concurrently, cytokine-mediated JAK/STAT signalling, particularly IL-6/STAT3, integrates signals from immune cells, ferroptotic processes, and microbial metabolites, positioning it as a central regulatory axis in endometriosis. This review synthesizes mechanistic data linking alterations in the gut microbiota, microbial metabolites, ferroptosis, and JAK/STAT signalling in the inflammatory microenvironment of endometriosis. While direct causal evidence remains limited, converging findings from preclinical and translational studies suggest that the microbiota-ferroptosis-JAK/STAT interaction network forms an interconnected system that contributes to sustained inflammation. Our discussion brings these mechanisms into a shared framework, suggesting that their combined influence may give clearer insight into endometriosis. We propose that exploring these molecular pathways may open new avenues for microbiota- and ferroptosis-informed strategies that target inflammation while preserving fertility. Similar content being viewed by others Data availability No datasets were generated or analysed during the current study. Change history 14 April 2026 Grant number in the funding section has been corrected as “FRGS/FP011-2023/UM”. Abbreviations - AGER: - Advanced Glycation End-product Receptor - Akt: - Protein kinase B - COX-2: - Cyclooxygenase-2 - GnRH: - Gonadotropin-releasing Hormone - GPX4: - Glutathione peroxidase 4 - GSH: - Glutathione - IFN-γ: - Interferon-gamma - IL-1: - Interleukin-1 - IL-6: - Interleukin-6 - IL-8: - Interleukin-8 - JAK: - Janus Kinase - KIR: - Killer cell inhibitory receptor - MALAT1: - Metastasis-associated lung adenocarcinoma transcript 1 - MAPK/Erk1/2: - Mitogen-activated protein kinase / Extracellular signal–regulated kinase 1/2 - MCP-1: - Monocyte chemoattractant protein-1 - MIF: - Macrophage migration inhibitory factor - MMP: - Matrix metalloproteinase - NF-κB: - Nuclear Factor Kappa-light-chain-enhancer of Activated B cells - NRF2: - Nuclear factor erythroid 2–related factor 2 (NFE2L2) - SCFAs: - Short-chain fatty acids - SLC7A11: - Solute carrier family 7 member 11 - STAT: - Signal Transducer and Activator of Transcription - TFRC: - Transferrin receptor (protein 1) - TGF-β: - Transforming growth factor - TNF-α: - Tumor Necrosis Factor Alpha - VEGF: - Vascular endothelial growth factor

WHO, Endometriosis (2023) [Available from: https://www.who.int/news-room/fact-sheets/detail/endometriosis Saunders PTK, Horne AW (2021) Endometriosis: etiology, pathobiology, and therapeutic prospects. Cell 184(11):2807–2824 Della Corte L, Di Filippo C, Gabrielli O, Reppuccia S, La Rosa VL, Ragusa R et al (2020) The burden of endometriosis on women’s lifespan: a narrative overview on quality of life and psychosocial wellbeing. Int J Environ Res Public Health 17(13):4683 Armour M, Lawson K, Wood A, Smith CA, Abbott J (2019) The cost of illness and economic burden of endometriosis and chronic pelvic pain in Australia: a national online survey. PLoS ONE 14(10):e0223316 Nisolle M, Donnez J (1997) Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 68(4):585–596 Lin Y-H, Chen Y-H, Chang H-Y, Au H-K, Tzeng C-R, Huang Y-H (2018) Chronic niche inflammation in endometriosis-Associated infertility: current understanding and future therapeutic strategies. Int J Mol Sci 19(8):2385 Hu X, li J, Fu M, Zhao X, Wang W (2021) The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 6(1):402 Omidvar-Mehrabadi A, Ebrahimi F, Shahbazi M, Mohammadnia-Afrouzi M (2024) Cytokine and chemokine profiles in women with endometriosis, polycystic ovary syndrome, and unexplained infertility. Cytokine 178:156588 Chen Y, Fang Z-M, Yi X, Wei X, Jiang D-S (2023) The interaction between ferroptosis and inflammatory signaling pathways. Cell Death Dis. https://doi.org/10.1038/s41419-023-05716-0 Lee H, Pal SK, Reckamp K, Figlin RA, Yu H (2010) STAT3: a target to enhance antitumor immune response. STAT3: A Target to Enhance Antitumor Immune Response. Springer Berlin Heidelberg, pp 41–59 Ho M, Nguyen H-N, Van Hoang M, Bui TTT, Vu B-Q, Dinh THT et al (2024) Altered skin microbiome, inflammation, and JAK/STAT signaling in Southeast Asian ichthyosis patients. Hum Genomics. https://doi.org/10.1186/s40246-024-00603-x Jiang I, Yong PJ, Allaire C, Bedaiwy MA (2021) Intricate connections between the microbiota and endometriosis. Int J Mol Sci 22(11):5644 Ata B, Yildiz S, Turkgeldi E, Brocal VP, Dinleyici EC, Moya A et al (2019) The endobiota study: comparison of vaginal, cervical and gut microbiota between women with stage 3/4 endometriosis and healthy controls. Sci Rep 9(1):2204 Yuan M, Li D, Zhang Z, Sun H, An M, Wang G (2018) Endometriosis induces gut microbiota alterations in mice. Hum Reprod 33(4):607–616 Salmeri N, Sinagra E, Dolci C, Buzzaccarini G, Sozzi G, Sutera M et al (2023) Microbiota in irritable bowel syndrome and endometriosis: birds of a feather flock together—a review. Microorganisms 11(8):2089 Barra F, Grandi G, Tantari M, Scala C, Facchinetti F, Ferrero S (2019) A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opin Biol Ther 19(4):343–360 Lin YH, Chen YH, Chang HY, Au HK, Tzeng CR, Huang YH (2018) Chronic niche inflammation in endometriosis-associated infertility: current understanding and future therapeutic strategies. Int J Mol Sci. https://doi.org/10.3390/ijms19082385 Symons LK, Miller JE, Kay VR, Marks RM, Liblik K, Koti M et al (2018) The immunopathophysiology of endometriosis. Trends Mol Med 24(9):748–62 Vallvé-Juanico J, Santamaria X, Vo KC, Houshdaran S, Giudice LC (2019) Macrophages display proinflammatory phenotypes in the eutopic endometrium of women with endometriosis with relevance to an infectious etiology of the disease. Fertil Steril 112(6):1118–1128 Hogg C, Horne AW, Greaves E (2020) Endometriosis-associated macrophages: origin, phenotype, and function. Front Endocrinol (Lausanne) 11:7 Oală IE, Mitranovici M-I, Chiorean DM, Irimia T, Crișan AI, Melinte IM et al (2024) Endometriosis and the role of pro-inflammatory and anti-inflammatory cytokines in pathophysiology: a narrative review of the literature. Diagnostics 14(3):312 Gogacz M, Winkler I, Bojarska-Junak A, Tabarkiewicz J, Semczuk A, Rechberger T et al (2016) Increased percentage of Th17 cells in peritoneal fluid is associated with severity of endometriosis. J Reprod Immunol 117:39–44 Knez J, Kovačič B, Goropevšek A (2024) The role of regulatory T-cells in the development of endometriosis. Hum Reprod 39(7):1367–1380. https://doi.org/10.1093/humrep/deae103 Milewski Ł, Dziunycz P, Barcz E, Radomski D, Roszkowski PI, Korczak-Kowalska G et al (2011) Increased levels of human neutrophil peptides 1, 2, and 3 in peritoneal fluid of patients with endometriosis: association with neutrophils, T cells and IL-8. J Reprod Immunol 91(1–2):64–70 García-Gómez E, Vázquez-Martínez ER, Reyes-Mayoral C, Cruz-Orozco OP, Camacho-Arroyo I, Cerbón M (2019) Regulation of inflammation pathways and inflammasome by sex steroid hormones in endometriosis. Front Endocrinol (Lausanne) 10:935 Liu Y, Wang J, Zhang X (2022) An update on the multifaceted role of NF-kappaB in endometriosis. Int J Biol Sci 18(11):4400–4413 Incognito GG, Di Guardo F, Gulino FA, Genovese F, Benvenuto D, Lello C et al (2023) Interleukin-6 as a useful predictor of endometriosis-associated infertility: a systematic review. Int J Fertil Steril 17(4):226–30 Yu J, Francisco AM, Patel BG, Cline JM, Zou E, Berga SL et al (2018) IL-1β stimulates brain-derived neurotrophic factor production in eutopic endometriosis stromal cell cultures: a model for cytokine regulation of neuroangiogenesis. Am J Pathol 188(10):2281–92 Reddy VP (2023) Oxidative stress in health and disease. Biomedicines. https://doi.org/10.3390/biomedicines11112925 Wyatt J, Fernando SM, Powell SG, Hill CJ, Arshad I, Probert C et al (2023) The role of iron in the pathogenesis of endometriosis: a systematic review. Hum Reprod Open 2023(3):hoad033 Santana-Codina N, Del Rey MQ, Kapner KS, Zhang H, Gikandi A, Malcolm C et al (2022) NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron-sulfur cluster proteins. Cancer Discov 12(9):2180–97 Malesza IJ, Bartkowiak-Wieczorek J, Winkler-Galicki J, Nowicka A, Dzięciołowska D, Błaszczyk M et al (2022) The dark side of iron: the relationship between iron, inflammation and gut microbiota in selected diseases associated with iron deficiency anaemia—a narrative review. Nutrients 14(17):3478 Wölfler MM, Meinhold-Heerlein IM, Henkel C, Rath W, Neulen J, Maass N et al (2013) Reduced hemopexin levels in peritoneal fluid of patients with endometriosis. Fertil Steril 100(3):777–781 e2 Woo JH, Choi YS, Choi JH (2020) Iron-storage protein ferritin is upregulated in endometriosis and iron overload contributes to a migratory phenotype. Biomedicines. https://doi.org/10.3390/biomedicines8110454 Lousse J-C, Van Langendonckt A, Defrere S, Ramos RG, Colette S, Donnez J (2012) Peritoneal endometriosis is an inflammatory disease. Front Biosci-Elite 4(1):23–40 Lousse J-C, Defrère S, Van Langendonckt A, Gras J, González-Ramos R, Colette S et al (2009) Iron storage is significantly increased in peritoneal macrophages of endometriosis patients and correlates with iron overload in peritoneal fluid. Fertil Steril 91(5):1668–75 Koninckx P, Kennedy S, Barlow D (1998) Endometriotic disease: the role of peritoneal fluid. Hum Reprod Update 4(5):741–751 Sousa Gerós A, Simmons A, Drakesmith H, Aulicino A, Frost JN (2020) The battle for iron in enteric infections. Immunology 161(3):186–199 Dostal A, Fehlbaum S, Chassard C, Zimmermann MB, Lacroix C (2013) Low iron availability in continuous in vitro colonic fermentations induces strong dysbiosis of the child gut microbial consortium and a decrease in main metabolites. FEMS Microbiol Ecol 83(1):161–175 Chadchan SB, Popli P, Ambati CR, Tycksen E, Han SJ, Bulun SE et al (2021) Gut microbiota–derived short-chain fatty acids protect against the progression of endometriosis. Life Sci Alliance 4(12):e202101224 Zhang Y, Liu X, Deng M, Xu C, Zhang Y, Wu D et al (2022) Ferroptosis induced by iron overload promotes fibrosis in ovarian endometriosis and is related to subpopulations of endometrial stromal cells. Front Pharmacol. https://doi.org/10.3389/fphar.2022.930614 Xue C, Yao Q, Gu X, Shi Q, Yuan X, Chu Q et al (2023) Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther 8(1):204 Hu Q, Bian Q, Rong D, Wang L, Song J, Huang HS et al (2023) JAK/STAT pathway: extracellular signals, diseases, immunity, and therapeutic regimens. Front Bioeng Biotechnol 11:1110765 Bharadwaj U, Kasembeli MM, Robinson P, Tweardy DJ (2020) Targeting Janus kinases and signal transducer and activator of transcription 3 to treat inflammation, fibrosis, and cancer: rationale, progress, and caution. Pharmacol Rev 72(2):486–526 Lokau J, Schoeder V, Haybaeck J, Garbers C (2019) Jak-Stat signaling induced by interleukin-6 family cytokines in hepatocellular carcinoma. Cancers (Basel). https://doi.org/10.3390/cancers11111704 Cacciapaglia F, Perniola S, Stano S, Venerito V, Natuzzi D, Bizzoca R et al (2025) Modulation of IL-6 receptor/STAT3 downstream signaling in rheumatoid arthritis patients. Exp Mol Pathol 141:104951 Xu J, Lin H, Wu G, Zhu M, Li M (2021) IL-6/STAT3 is a promising therapeutic target for hepatocellular carcinoma. Front Oncol. ;Volume 11–2021 Park Y, Han SJ (2022) Interferon signaling in the endometrium and in endometriosis. Biomolecules. https://doi.org/10.3390/biom12111554 Günther C, Ruder B, Stolzer I, Dorner H, He G-W, Chiriac MT et al (2019) Interferon lambda promotes Paneth cell death via STAT1 signaling in mice and is increased in inflamed ileal tissues of patients with crohn’s disease. Gastroenterology 157(5):1310–22e13 Hu Y, Chen H, Jin L, Chi X, Zhao J, Cao Q (2025) Hypomethylation of IL6ST promotes development of endometriosis by activating JAK2/STAT3 signaling pathway. PLoS One 20(1):e0317569 Bian Y, Yuan L, Yang X, Weng L, Zhang Y, Bai H et al (2021) Smurf1-mediated ubiquitylation of SHP-1 promotes cell proliferation and invasion of endometrial stromal cells in endometriosis. Ann Transl Med 9(5):362 Matsuzaki S, Pouly JL, Canis M (2022) Persistent activation of signal transducer and activator of transcription 3 via interleukin-6 trans-signaling is involved in fibrosis of endometriosis. Hum Reprod 37(7):1489–1504 Kim BG, Yoo J-Y, Kim TH, Shin J-H, Langenheim JF, Ferguson SD et al (2015) Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis. Hum Reprod 30(5):1069–78 Xu Y, Wu F, Qin C, Lin Y (2023) Paradoxical role of phosphorylated STAT3 in normal fertility and the pathogenesis of adenomyosis and endometriosis†. Biol Reprod 110(1):5–13 Geng R, Huang X, Li L, Guo X, Wang Q, Zheng Y (2022) Gene expression analysis in endometriosis: immunopathology insights, transcription factors and therapeutic targets. Front Immunol. https://doi.org/10.3389/fimmu.2022.1037504 Lee H, Herrmann A, Deng J-H, Kujawski M, Niu G, Li Z et al (2009) Persistently activated Stat3 maintains constitutive NF-κB activity in tumors. Cancer Cell 15(4):283–293 Dalwadi H, Krysan K, Heuze-Vourc’H N, Dohadwala M, Elashoff D, Sharma S et al (2005) Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by Interleukin-6 in non–small cell lung cancer. Clin Cancer Res 11(21):7674–82 Lai Z-Z, Yang H-L, Ha S-Y, Chang K-K, Mei J, Zhou W-J et al (2019) Cyclooxygenase-2 in endometriosis. Int J Biol Sci 15(13):2783–97 Lin K, Ma J, Peng Y, Sun M, Xu K, Wu R et al (2019) Autocrine production of Interleukin-34 promotes the development of endometriosis through CSF1R/JAK3/STAT6 signaling. Sci Rep 9(1):16781 Miller JE, Monsanto SP, Ahn SH, Khalaj K, Fazleabas AT, Young SL et al (2017) Interleukin-33 modulates inflammation in endometriosis. Sci Rep. https://doi.org/10.1038/s41598-017-18224-x Pei Y, Cui X, Wang Y (2024) Regulation of IL-10 expression and function by JAK-STAT in CD8 + T cells. Int Immunopharmacol 128:111563 Wang Y, Nie XB, Liu SJ, Liu J, Bian WH (2022) Curcumol attenuates endometriosis by inhibiting the JAK2/STAT3 signaling pathway. Med Sci Monit 28:e934914 Kotlyar AM, Mamillapalli R, Flores VA, Taylor HS (2021) Tofacitinib alters STAT3 signaling and leads to endometriosis lesion regression. Mol Hum Reprod. https://doi.org/10.1093/molehr/gaab016 Inui H, Kawakita T, Murayama M, Nakagawa T, Sasada H, Shinohara A et al (2023) Effects of STAT inhibitors in mouse models of endometriosis. Reprod Sci 30(8):2449–56 Golinska M, Rycerz A, Sobczak M, Chrzanowski J, Stawiski K, Fendler W (2025) Complement and coagulation cascade cross-talk in endometriosis and the potential of Janus Kinase inhibitors-a network metaanalysis. Front Immunol 16:1619434 Ponniah Subramanian AR, Chithrabhanu A, Venugopal R, Narayanswamy S, Periaswamy V (2025) Is JAK inhibitor a therapeutic option for endometriosis? The Journal of Obstetrics and Gynecology of India 75(Suppl 1):585–8 Huttenhower C, Gevers D, Knight R, Abubucker S, Badger JH, Chinwalla AT et al (2012) Structure, function and diversity of the healthy human Microbiome. Nature 486(7402):207–214 Zeng MY, Inohara N, Nuñez G (2017) Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol 10(1):18–26 Zeng L, Qian Y, Cui X, Zhao J, Ning Z, Cha J et al (2025) Immunomodulatory role of gut microbial metabolites: mechanistic insights and therapeutic frontiers. Front Microbiol 16:1675065. https://doi.org/10.3389/fmicb.2025.1675065} Kunst C, Schmid S, Michalski M, Tümen D, Buttenschön J, Müller M et al (2023) The influence of gut microbiota on oxidative stress and the immune system. Biomedicines 11(5):1388 Le N, Cregger M, Fazleabas A, Braundmeier-Fleming A (2022) Effects of endometriosis on immunity and mucosal microbial community dynamics in female Olive baboons. Sci Rep 12(1):1590 Malvezzi H, Cestari BA, Mendes H, Hernandes C, Podgaec S (2025) Peritoneal fluid microbiota profile of patients with deep endometriosis. Microb Pathog 199:107244 Ivashkin V, Poluektov Y, Kogan E, Shifrin O, Sheptulin A, Kovaleva A et al (2021) Disruption of the pro-inflammatory, anti-inflammatory cytokines and tight junction proteins expression, associated with changes of the composition of the gut microbiota in patients with irritable bowel syndrome. PLoS One 16(6):e0252930 Chelakkot C, Ghim J, Ryu SH (2018) Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med 50(8):1–9 Chen L, Zhang L, Hua H, Liu L, Mao Y, Wang R (2024) Interactions between toll-like receptors signaling pathway and gut microbiota in host homeostasis. Immunity Inflamm Dis 12(7):e1356 El Houdi M, Skhoun H, Guennoun A, Dakka N, Ameziane El Hassani R, Ouzzif Z et al (2025) Deciphering TLR and JAK/STAT pathways: genetic variants and targeted therapies in COVID-19. Mol Biol Rep 52(1):733 Lei H, Crawford MS, McCole DF (2021) JAK-STAT pathway regulation of intestinal permeability: pathogenic roles and therapeutic opportunities in inflammatory bowel disease. Pharmaceuticals (Basel). https://doi.org/10.3390/ph14090840 Mohling SI, Holcombe J, Furr RS (2023) Intestinal permeability and endometriosis: a pilot investigation. J Endometr Uterine Disord 3:100045 Li Z, Wang F, Kang E, Zhen X, Liu J, Wang W (2025) The role of endometriosis in intestinal inflammation: a combined Mendelian randomization and cellular study. J Cell Mol Med 29(17):e70799 Sobstyl M, Niedźwiedzka-Rystwej P, Grywalska E, Korona-Głowniak I, Sobstyl A, Bednarek W et al (2020) Toll-like receptor 2 expression as a new hallmark of advanced endometriosis. Cells. https://doi.org/10.3390/cells9081813 Liu J, Tan Y, Cheng H, Zhang D, Feng W, Peng C (2022) Functions of gut microbiota metabolites, current status and future perspectives. Aging Dis 13(4):1106–1126 Du Y, He C, An Y, Huang Y, Zhang H, Fu W et al (2024) The role of short chain fatty acids in inflammation and body health. Int J Mol Sci 25(13):7379 Wu Q, Ge Z, Lv C, He Q (2025) Interacting roles of gut microbiota and T cells in the development of autoimmune hepatitis. Front Immunol 16:1584001. https://doi.org/10.3389/fimmu.2025.1584001 Lu Z, Yu L, Bai Y, Cui Y, Shi M, Li Z et al (2025) The potential mechanisms of reciprocal regulation of gut microbiota-liver immune signaling in metabolic dysfunction-associated steatohepatitis revealed in multi-omics analysis. mSystems 10(7):e00518–e00525 Damerau A, Gaber T, Ohrndorf S, Hoff P (2020) JAK/STAT activation: a general mechanism for bone development, homeostasis, and regeneration. Int J Mol Sci 21(23):9004 Hufnagel D, Li F, Cosar E, Krikun G, Taylor HS (2015) The Role of stem cells in the etiology and pathophysiology of endometriosis. Semin Reprod Med 33(5):333–340. https://doi.org/10.1055/s-0035-1564609 Kwon O, Lee S, Kim J-H, Kim H, Lee S-W (2015) Altered gut microbiota composition in Rag1-deficient mice contributes to modulating homeostasis of hematopoietic stem and progenitor cells. Immune Netw 15(5):252–259 Xu Y, Zhu Y, Wu X, Peng W, Zhong Y, Cai Y et al (2025) Gut microbiota-derived acetate ameliorates endometriosis via JAK1/STAT3-mediated M1 macrophage polarisation. Microb Biotechnol 18(8):e70202 Li Y, Yang X, Han J, Bai B, Li Y, Shang C et al (2024) Peimisine ameliorates DSS-induced colitis by suppressing Jak–Stat activation and alleviating gut microbiota dysbiosis in mice. J Pharm Pharmacol 76(5):545–58 Yang H, Li S, Qu Y, Li L, Li Y, Wang D (2022) Anti-colorectal cancer effects of inonotus hispidus (Bull.: Fr.) P. Karst. spore powder through regulation of gut microbiota-mediated JAK/STAT signaling. Nutrients 14(16):3299 Zhang Y-G, Lu R, Wu S, Chatterjee I, Zhou D, Xia Y et al (2020) Vitamin D receptor protects against dysbiosis and tumorigenesis via the JAK/STAT pathway in intestine. Cell Mol Gastroenterol Hepatol 10(4):729–46 Hong Z-S, Xie J, Wang X-F, Dai J-J, Mao J-Y, Bai Y-Y et al (2022) Moringa oleifera Lam. peptide remodels intestinal mucosal barrier by inhibiting JAK-STAT activation and modulating gut microbiota in colitis. Front Immunol. https://doi.org/10.3389/fimmu.2022.924178 Wang L, Xian Y-F, Loo SKF, Ip SP, Yang W, Chan WY et al (2022) Baicalin ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice through modulating skin barrier function, gut microbiota and JAK/STAT pathway. Bioorg Chem 119:105538 Wang J, Zhu G, Sun C, Xiong K, Yao T, Su Y et al (2020) TAK-242 ameliorates DSS-induced colitis by regulating the gut microbiota and the JAK2/STAT3 signaling pathway. Microb Cell Fact. https://doi.org/10.1186/s12934-020-01417-x Gu X, Miao Z, Wang Y, Yang Y, Yang T, Xu Y (2022) New Baitouweng decoction combined with fecal microbiota transplantation alleviates DSS-induced colitis in rats by regulating gut microbiota metabolic homeostasis and the STAT3/NF-κB signaling pathway. BMC Complement Med Ther. https://doi.org/10.1186/s12906-022-03766-z Dixon SJ, Olzmann JA (2024) The cell biology of ferroptosis. Nat Rev Mol Cell Biol 25(6):424–442 Wen Q, Liu J, Kang R, Zhou B, Tang D (2019) The release and activity of HMGB1 in ferroptosis. Biochem Biophys Res Commun 510(2):278–283 Dai Y, Cui C, Jiao D, Zhu X (2025) JAK/STAT signaling as a key regulator of ferroptosis: mechanisms and therapeutic potentials in cancer and diseases. Cancer Cell Int 25(1):83 Cao T, Zhou J, Liu Q, Mao T, Chen B, Wu Q et al (2023) Interferon-γ induces salivary gland epithelial cell ferroptosis in Sjogren’s syndrome via JAK/STAT1-mediated inhibition of system Xc. Free Radic Biol Med 205:116–28 Mo M, Pan L, Deng L, Liang M, Xia N, Liang Y (2024) Iron overload induces hepatic ferroptosis and insulin resistance by inhibiting the Jak2/stat3/slc7a11 signaling pathway. Cell Biochem Biophys 82(3):2079–2094 Li Y, Zhang Y, Qiu Q, Wang L, Mao H, Hu J et al (2022) Energy-stress-mediated AMPK activation promotes GPX4-dependent ferroptosis through the JAK2/STAT3/P53 axis in renal cancer. Oxid Med Cell Longev 2022(1):2353115 Zhang Z, He Y, Liu H, Liu Y, Wu T, Li R et al (2024) NLRP3 regulates ferroptosis via the JAK2/STAT3 pathway in asthma inflammation: insights from in vivo and in vitro studies. Int Immunopharmacol 143:113416 Xiong J, Zhou R, Deng X (2024) PRDX6 alleviated heart failure by inhibiting doxorubicin-induced ferroptosis through the JAK2/STAT1 pathway inactivation. Vitro Cell Dev Biology - Anim 60(4):354–364 Chen W-j, Pan X-w, Song X, Liu Z-c, Xu D, Chen J-x et al (2024) Preoperative neoadjuvant targeted therapy remodels intra-tumoral heterogeneity of clear-cell renal cell carcinoma and ferroptosis inhibition induces resistance progression. Cancer Lett 593:216963 Wang Z, Zong H, Liu W, Lin W, Sun A, Ding Z et al (2024) Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11. J Exp Clin Cancer Res 43(1):112 Huang C-Y, Chen L-J, Chen G, Chao T-I, Wang C-Y (2022) SHP-1/STAT3-signaling-axis-regulated coupling between BECN1 and SLC7A11 contributes to Sorafenib-induced ferroptosis in hepatocellular carcinoma. Int J Mol Sci 23(19):11092 Xu X, Zhu M, Zu Y, Wang G, Li X, Yan J (2024) Nox2 inhibition reduces trophoblast ferroptosis in preeclampsia via the STAT3/GPX4 pathway. Life Sci 343:122555 Liu Q, Wang K (2019) The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin. Cell Biol Int 43(11):1245–1256 Miao M, Pan M, Chen X, Shen J, Zhang L, Feng X et al (2024) IL-13 facilitates ferroptotic death in asthmatic epithelial cells via SOCS1-mediated ubiquitinated degradation of SLC7A11. Redox Biol 71:103100 Yang Q, Xia Y, Chen K, Wang Y, Song D, Zhu J et al (2024) Blue light induced ferroptosis via STAT3/GPX4/SLC7A11/FTH1 in conjunctiva epithelium in vivo and in vitro. J Photochem Photobiol B Biol 255:112908 Yu X, Zhu D, Luo B, Kou W, Cheng Y, Zhu Y (2022) IFNγ enhances ferroptosis by increasing JAK‑STAT pathway activation to suppress SLCA711 expression in adrenocortical carcinoma. Oncol Rep. https://doi.org/10.3892/or.2022.8308 Wei T-T, Zhang M-Y, Zheng X-H, Xie T-H, Wang W, Zou J et al (2022) Interferon-γ induces retinal pigment epithelial cell ferroptosis by a JAK1-2/STAT1/SLC7A11 signaling pathway in age-related macular degeneration. FEBS J 289(7):1968–83 Li Y, He Y, Cheng W, Zhou Z, Ni Z, Yu C (2023) Double-edged roles of ferroptosis in endometriosis and endometriosis-related infertility. Cell Death Discov 9(1):306 Li G, Lin Y, Zhang Y, Gu N, Yang B, Shan S et al (2022) Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis. Cell Death Discov 8(1):29 Wu Q, Liang Z, Jiang J, Feng X, Liu J, Zhang Z et al (2023) Macrophages originated IL-33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis. Cell Death Dis 14(10):668 Lao J, Hu P, Wan Y, Shu M, Chen J, Yang H (2024) NEDD4 knockdown suppresses human endometrial stromal cell growth and invasion by regulating PTGS2-Mediated ferroptosis in endometriosis. Curr Mol Med 25(9):1154-1166. https://doi.org/10.2174/0115665240311438241011052341 Wan Y, Gu C, Kong J, Sui J, Zuo L, Song Y et al (2022) Long noncoding RNA ADAMTS9-AS1 represses ferroptosis of endometrial stromal cells by regulating the miR-6516-5p/GPX4 axis in endometriosis. Sci Rep. https://doi.org/10.1038/s41598-022-04963-z Dai E, Han L, Liu J, Xie Y, Kroemer G, Klionsky DJ et al (2020) Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 16(11):2069–2083 Dai E, Han L, Liu J, Xie Y, Zeh HJ, Kang R et al (2020) Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat Commun 11(1):6339 Fu Z, Liu H, Kuang Y, Yang J, Luo M, Cao L et al (2025) β-elemene, a sesquiterpene constituent from Curcuma phaeocaulis inhibits the development of endometriosis by inducing ferroptosis via the MAPK and STAT3 signaling pathways. J Ethnopharmacol 341:119344 Gou Y, Ding J, Wang H, Bai R, Wang H, Wang B et al (2025) Gut microbiota derived butyrate enhances ferroptosis sensitivity in endometriosis through FFAR2/PPAR-γ/PINK1/Parkin mediated mitophagy. Free Radic Biol Med 238:640–52 Khera R, Mehan S, Kumar S, Sethi P, Bhalla S, Prajapati A (2022) Role of JAK-STAT and PPAR-Gamma signalling modulators in the prevention of autism and neurological dysfunctions. Mol Neurobiol 59(6):3888–3912 Wang X, Pan L, Niu D, Zhou J, Shen M, Zeng Z et al (2025) Jingfang granules alleviates the lipid peroxidation induced ferroptosis in rheumatoid arthritis rats by regulating gut microbiota and metabolism of short chain fatty acids. J Ethnopharmacol 339:119160 Dar HH, Tyurina YY, Mikulska-Ruminska K, Shrivastava I, Ting H-C, Tyurin VA et al (2019) Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium. J Clin Investig 128(10):4639–4653 Amaral EP, Costa DL, Namasivayam S, Riteau N, Kamenyeva O, Mittereder L et al (2019) A major role for ferroptosis in Mycobacterium tuberculosis–induced cell death and tissue necrosis. J Exp Med 216(3):556–70 Yang M, Lu Z, Li F, Shi F, Zhan F, Zhao L et al (2021) Escherichia coli induced ferroptosis in red blood cells of grass carp (Ctenopharyngodon idella). Fish Shellfish Immunol 112:159–67 Furumoto H, Nanthirudjanar T, Kume T, Izumi Y, Park S-B, Kitamura N et al (2016) 10-oxo-trans-11-octadecenoic acid generated from linoleic acid by a gut lactic acid bacterium Lactobacillus plantarum is cytoprotective against oxidative stress. Toxicol Appl Pharmacol 296:1–9 Liu Y, Wang L, Huang T, Li Y, Zhang H (2024) Integrative gut microbiota and metabolomic analyses reveal the PANoptosis- and Ferroptosis-Related mechanisms of chrysoeriol in inhibiting melanoma. J Agric Food Chem 72(45):25173–25185 Ge H, Wei Y, Zhang W, Yong C, Chen Y, Zhou E (2024) Suyin detoxification granule alleviates trimethylamine N-oxide–induced tubular ferroptosis and renal fibrosis to prevent chronic kidney disease progression. Phytomedicine 135:156195 Zhu X, Lu H, Li W, Niu S, Xue J, Sun H et al (2025) Ferroptosis induces gut microbiota and metabolic dysbiosis in Collagen-Induced arthritis mice via PAD4 enzyme. Gene 936:149106 Ma Y, Li W, Niu S, Zhu X, Chu M, Wang W et al (2023) BzATP reverses ferroptosis-induced gut microbiota disorders in collagen-induced arthritis mice. Int Immunopharmacol 124:110885 Zhao C, Bao L, Shan R, Zhao Y, Wu K, Shang S et al (2025) Maternal gut inflammation aggravates acute liver failure through facilitating ferroptosis via altering gut microbial metabolism in offspring. Adv Sci 12(9):2411985 Peng G, Wang S, Zhang H, Xie F, Jiao L, Yuan Y et al (2024) Tremella aurantialba polysaccharides alleviate ulcerative colitis in mice by improving intestinal barrier via modulating gut microbiota and inhibiting ferroptosis. Int J Biol Macromol 281:135835 Yu H, Lin G, Jiang J, Yao J, Pan Z, Xie H et al (2024) Synergistic activity of Enterococcus faecium-induced ferroptosis via expansion of IFN-γ(+)CD8(+) T cell population in advanced hepatocellular carcinoma treated with sorafenib. Gut Microbes 16(1):2410474 Wang J, Yao Y, Yao T, Shi Q, Zeng Y, Li L (2024) Hesperetin alleviated experimental colitis via regulating ferroptosis and gut microbiota. Nutrients. https://doi.org/10.3390/nu16142343 Pi Y, Zuo H, Wang Y, Zheng W, Zhou H, Deng L et al (2024) Oleanolic acid alleviating ischemia-reperfusion injury in rat severe steatotic liver via KEAP1/NRF2/ARE. Int Immunopharmacol 138:112617 Zhang Q, Zhou J, Zhai D, Jiang Q, Yang M, Zhou M (2024) Gut microbiota regulates the ALK5/NOX1 axis by altering glutamine metabolism to inhibit ferroptosis of intrahepatic cholangiocarcinoma cells. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1870(5):167152 Wei J, Wang G, Lai M, Zhang Y, Li F, Wang Y et al (2024) Faecal microbiota transplantation alleviates ferroptosis after ischaemic stroke. Neuroscience 541:91–100 Wu H, Zhang P, Zhou J, Hu S, Hao J, Zhong Z et al (2024) Paeoniflorin confers ferroptosis resistance by regulating the gut microbiota and its metabolites in diabetic cardiomyopathy. Am J Physiol Cell Physiol 326(3):C724-c41 Cheng J, Liu D, Huang Y, Chen L, Li Y, Yang Z et al (2023) Phlorizin mitigates Dextran Sulfate Sodium-induced colitis in mice by modulating gut microbiota and inhibiting ferroptosis. J Agric Food Chem 71(43):16043–56 Wu Y, Ran L, Yang Y, Gao X, Peng M, Liu S et al (2023) Deferasirox alleviates DSS-induced ulcerative colitis in mice by inhibiting ferroptosis and improving intestinal microbiota. Life Sci 314:121312 Huang W, Chen H, He Q, Xie W, Peng Z, Ma Q et al (2023) Nobiletin protects against ferroptosis to alleviate sepsis-associated acute liver injury by modulating the gut microbiota. Food Funct 14(16):7692–7704 Wei XH, Liu YY (2023) Potential applications of JAK inhibitors, clinically approved drugs against autoimmune diseases, in cancer therapy. Front Pharmacol 14:1326281 Kour G, Choudhary R, Anjum S, Bhagat A, Bajaj BK, Ahmed Z (2022) Phytochemicals targeting JAK/STAT pathway in the treatment of rheumatoid arthritis: is there a future? Biochem Pharmacol 197:114929 Rah B, Rather RA, Bhat GR, Baba AB, Mushtaq I, Farooq M et al (2022) JAK/STAT signaling: molecular Targets, therapeutic Opportunities, and limitations of targeted inhibitions in solid malignancies. Front Pharmacol 13:821344 Luo Y, Alexander M, Gadina M, O’Shea JJ, Meylan F, Schwartz DM (2021) JAK-STAT signaling in human disease: from genetic syndromes to clinical inhibition. J Allergy Clin Immunol 148(4):911–925 Zhang D, Dong B, Chen J, Zhang Z, Zeng W, Liao L et al (2025) Fecal microbiota transplantation modulates Th17/Treg balance via JAK/STAT pathway in ARDS rats. Adv Biol 9(9):e00028 Xie L, Zhong Y, Chen Y, Wang Y, Xian P, Liu S et al (2025) Cryptotanshinone alleviates immunosuppression in endometriosis by targeting MDSCs through JAK2/STAT3 pathway. Phytomedicine 136:156227 Funding This work was financially supported by the Ministry of Higher Education Malaysia via the Fundamental Research Grant Scheme (FRGS/FP011-2023/UM). 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About this article Cite this article Shah, H., Salleh, N., Hamdan, M. et al. Molecular mechanisms in endometriosis: linking JAK/STAT pathway, ferroptosis, and microbial dysbiosis. Mol Biol Rep 53, 387 (2026). https://doi.org/10.1007/s11033-025-11401-6 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s11033-025-11401-6