From gut-reproductive microbiota to ferroptosis: a comprehensive insight into the molecular-pathogenicity of endometriosis

Xianhua Han, Xin lei Guo, Junyu Qiu
In: Frontiers in Immunology · 2026 · vol. 17 , pp. 1762013 · doi:10.3389/fimmu.2026.1762013 · PMID:42253950 · PMC13236934 · W7162087728
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This review proposes a new "dysbiosis–iron overload–ferroptosis" mechanism for endometriosis, integrating gut-reproductive microbiome imbalances and ferroptosis into its pathogenesis and suggesting therapeutic strategies.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 ⓘ

This review synthesizes evidence on how gut and reproductive tract microbiome imbalance, iron metabolism abnormalities, and ferroptosis-related molecular mechanisms intersect in endometriosis, integrating findings from microbiome studies and multi-omics approaches such as metabolomics and iron/ferroptosis marker analyses. It proposes a unified “dysbiosis–iron overload–ferroptosis” pathological framework in which microbial dysbiosis influences host iron homeostasis and inflammatory/metabolic environments, contributing to iron-dependent lipid peroxidation and ferroptosis activation, while endometriosis cells may partially resist ferroptosis via antioxidant pathways such as ATF4/xCT. The authors note key limitations and uncertainties including heterogeneity across cohorts (e.g., sampling, subtypes, diet, treatments) and incomplete clarification of whether microbial dysbiosis is a causal upstream driver or a secondary consequence, potentially involving bidirectional feedback loops rather than a unidirectional one. This paper is centrally about endometriosis — it systematically reviews the mechanistic link between gut-reproductive microbiome dysbiosis, iron overload, and ferroptosis in endometriosis pathogenesis.

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Abstract

Endometriosis (EMS) is a highly heterogeneous chronic gynecological disease characterized by pain, infertility, and relapse, with its etiology and pathogenesis not yet fully elucidated. Traditional theories, including "retrograde menstruation," "implantation theory," and "abnormalities in immune tolerance," struggle to adequately explain the complex lesion behavior, diverse phenotypic characteristics, and accompanying immune-metabolic disorders. In recent years, the key roles of imbalances in the gut and reproductive microbiomes, abnormal iron metabolism, and the newly proposed ferroptosis in the occurrence and development of EMS have gradually gained attention, suggesting that this disease may be a systemic condition involving the interplay of microbial ecology, iron metabolism, and cell death. Existing studies indicate that the gut-reproductive microbiome profoundly influences the body's iron homeostasis and iron load by regulating mucosal immunity, systemic inflammatory responses, and metabolic environments. This, in turn, activates the ferroptosis pathway through iron-dependent lipid peroxidation and cell membrane damage, participating in the formation, maintenance, and inflammatory microenvironment shaping of ectopic lesions. Based on these findings, this article systematically reviews the interactions between gut-reproductive microbiome imbalance and iron metabolism disorders, integrating multi-omics evidence such as microbiome analysis, metabolomics, and iron metabolism/ferroptosis-related molecular markers. It proposes a new pathological mechanism framework of "dysbiosis-iron overload-ferroptosis" incorporating microecological imbalance and ferroptosis into a unified picture of the pathogenesis of EMS. Furthermore, this article discusses potential therapeutic strategies and application prospects surrounding microbiome remodeling (such as probiotics, fecal microbiota transplantation, dietary and lifestyle interventions) and pharmacological targeting of key ferroptosis-related molecules. Through a comprehensive and critical analysis of existing evidence, this review aims to provide a more systematic theoretical framework for the mechanistic research of EMS and offer ideas and directions for future clinical translation of precise classification, individualized intervention, and novel treatment plans.

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Condition tags

endometriosisinfertility

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