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Objective <p>This study investigates the therapeutic potential of interleukin-22 (IL-22) in polycystic ovary syndrome (PCOS) and its mechanisms.</p> Methods <p>A dehydroepiandrosterone (DHEA)-induced PCOS mouse model and testosterone-treated human KGN granulosa cells were utilized. Mice received IL-22 (50–100&#xa0;µg/kg) or Diane-35 for 3 weeks.</p> Results <p>IL-22 administration restored estrous cyclicity, reduced ovarian cysts, and normalized serum testosterone and insulin levels in DHEA or letrozole-induced PCOS mice. DHEA induction led to mitochondrial damage in granulosa cells (GCs), evidenced by impaired mitochondrial membrane potential, mtDNA copy number depletion, and ROS accumulation, alongside lipid metabolic dysregulation. These detrimental effects were ameliorated by IL-22. Bioinformatics analysis of PCOS patient data revealed significant enrichment in lipid metabolism pathways. A high-fat diet abolished IL-22’s PCOS-restoring effects, underscoring lipid metabolism as a key mechanism. We identified 19 lipid metabolism-related genes, with ETS1 being the most significantly regulated. IL-22 inhibited ETS1 expression induced by DHEA through the activation of STAT3 dependent on the IL-22R1, and Chromatin Immunoprecipitation (ChIP)-PCR confirmed STAT3 binding to the <i>ETS1</i> promoter.</p> Conclusion <p>Our findings highlight IL-22 as a promising therapeutic candidate for PCOS, acting through the IL-22R1/STAT3/ETS1 pathway to ameliorate mitochondrial dysfunction and lipid metabolic reprogramming in GCs. This study bridges immune signaling with metabolic pathology in PCOS, offering novel avenues for targeted intervention.</p>

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IL-22/IL-22R signaling attenuates mitochondrial damage in PCOS by modulating granulosa cell lipid metabolism through ETS1

  • 期刊论文

  • 发表日期：

    2026年3月17日

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  • Man Luo,
  • Yuanyuan Chen,
  • Hongmei Chen,
  • Yi Wen

摘要

Objective

This study investigates the therapeutic potential of interleukin-22 (IL-22) in polycystic ovary syndrome (PCOS) and its mechanisms.

Methods

A dehydroepiandrosterone (DHEA)-induced PCOS mouse model and testosterone-treated human KGN granulosa cells were utilized. Mice received IL-22 (50–100 µg/kg) or Diane-35 for 3 weeks.

Results

IL-22 administration restored estrous cyclicity, reduced ovarian cysts, and normalized serum testosterone and insulin levels in DHEA or letrozole-induced PCOS mice. DHEA induction led to mitochondrial damage in granulosa cells (GCs), evidenced by impaired mitochondrial membrane potential, mtDNA copy number depletion, and ROS accumulation, alongside lipid metabolic dysregulation. These detrimental effects were ameliorated by IL-22. Bioinformatics analysis of PCOS patient data revealed significant enrichment in lipid metabolism pathways. A high-fat diet abolished IL-22’s PCOS-restoring effects, underscoring lipid metabolism as a key mechanism. We identified 19 lipid metabolism-related genes, with ETS1 being the most significantly regulated. IL-22 inhibited ETS1 expression induced by DHEA through the activation of STAT3 dependent on the IL-22R1, and Chromatin Immunoprecipitation (ChIP)-PCR confirmed STAT3 binding to the ETS1 promoter.

Conclusion

Our findings highlight IL-22 as a promising therapeutic candidate for PCOS, acting through the IL-22R1/STAT3/ETS1 pathway to ameliorate mitochondrial dysfunction and lipid metabolic reprogramming in GCs. This study bridges immune signaling with metabolic pathology in PCOS, offering novel avenues for targeted intervention.