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The study aims to explore the roles of immune dysregulation and ferroptosis in the development of PCOS.

July 24, 2026Open Access

Identification and Validation of Genes Involved in Immune and Ferroptosis in Polycystic Ovarian Syndrome Using Bioinformatics and Experimental Approach

YCYang ChenYunnan Maternal and Child Health LXLiwei XingShanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine ZHZhe HeYunnan Provincial Hospital of Traditional Chinese Medicine

Key Points

The study aims to explore the roles of immune dysregulation and ferroptosis in the development of PCOS.
Integrated multiple GEO datasets to screen differentially expressed genes.
Used weighted gene co‑expression network analysis and machine learning algorithms for candidate gene identification.
Conducted in vitro and in vivo experiments to examine the effects of DHT and NNMT on ferroptosis.
DEGs were enriched in immune response and ferroptosis pathways, with 12 candidate genes showing diagnostic potential.
DHT treatment increased ferroptosis markers in KGN cells, with effective reversal by ferroptosis inhibitors.
PCOS mouse model presented pathological ovarian changes, elevated NNMT, and abnormal ferroptosis pathway activation.

Abstract

BACKGROUND: Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine and metabolic disease. This study aimed to investigate the synergistic role of immune dysregulation and ferroptosis during the pathogenesis of PCOS. METHODS: Through integrating multiple Gene Expression Omnibus (GEO) datasets, differentially expressed genes (DEGs) were screened and subjected to functional enrichment analysis; weighted gene co‑expression network analysis combined with LASSO, RandomForest, and support vector machine‑recursive feature elimination algorithms were employed to identify key candidate genes; in vitro, human ovarian granulosa cells (KGN) were treated with dihydrotestosterone (DHT), NNMT expression was regulated via lentiviral vectors together with ferroptosis inhibitor intervention, and cell viability, cytotoxicity, and ferroptosis‑related indicators were examined; in vivo, a PCOS mouse model was established using dehydroepiandrosterone, and ovarian pathology, hormone levels, as well as molecular expression of the ferroptosis pathway were analyzed. RESULTS: DEGs in PCOS were significantly enriched in immune response and ferroptosis pathways. Twelve candidate genes were identified through screening multiple GEO datasets and demonstrated diagnostic potential. DHT induced ferroptosis in KGN cells by upregulating NNMT, manifesting as reduced cell viability, increased LDH release, accompanied by Fe²⁺ accumulation, enhanced lipid peroxidation, downregulation of SLC7A11/GPX4, and upregulation of ACSL4. This process could be partially reversed by ferroptosis inhibitors. Knockdown of NNMT effectively alleviated the DHT‑induced ferroptosis phenotype. Ovaries from PCOS mice exhibited typical pathological alterations, concurrent with elevated NNMT expression and abnormal activation of the ferroptosis pathway. CONCLUSION: This study has uncovered novel mechanisms underlying the development and progression of PCOS, offering potential targets for its diagnosis and treatment.

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