HSD11B1 suppresses ferroptosis in endometrial stromal cells through the JUND/IL-10 axis to promote endometriosis...

Endometriosis (EMs) is a common gynecological disorder characterized by ectopic endometrial tissue growth, leading to chronic inflammation and pelvic pain. Despite its high prevalence, the molecular mechanisms underlying EMs remain poorly understood. This study aims to identify key biomarkers and elucidate the role of ferroptosis in EMs pathogenesis.

We integrated machine learning approaches with single-cell transcriptomic analysis to screen for ferroptosis-related genes in EMs. Candidate genes were prioritized based on differential expression and diagnostic performance. Functional validation was conducted using in vitro and in vivo models, including primary ectopic endometrial stromal cells (EESCs) and a mouse model of EMs.

HSD11B1 was identified as a core ferroptosis-related gene with high diagnostic value. Mechanistically, elevated HSD11B1 expression upregulated the transcription factor JUND, which directly bound to the IL-10 promoter and enhanced its expression. This HSD11B1/JUND/IL-10 axis suppressed ferroptosis in EESCs, as evidenced by increased cell viability, reduced lipid peroxidation, decreased Fe²⁺ and malondialdehyde levels, and preserved mitochondrial morphology. Knockdown of HSD11B1 or JUND reversed these effects, while IL-10 overexpression partially rescued the ferroptosis-resistant phenotype. Elevated expression of HSD11B1, JUND, and IL-10 was further confirmed in ectopic lesions from both EMs mouse models and patient samples.

Our findings identify HSD11B1 as a key regulator of ferroptosis in endometriosis via the JUND/IL-10 signaling axis, suggesting that HSD11B1 may serve as a potential non-invasive biomarker and a candidate therapeutic target for EMs pending further clinical validation.