Heme oxygenase-1 emerges as a critical regulator linking autophagy dysregulation, immune infiltration, and NOD-Like receptor signaling in PCOS pathogenesis
Abstract
Background: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder increasingly recognized to involve chronic inflammation, autophagy dysfunction, and immune imbalance. The molecular mechanisms connecting autophagy-related genes (ATGs), immune infiltration, and ovarian dysfunction remain unclear.
Methods: Transcriptomic data from ovarian granulosa cells (GSE34526 and GSE137684) were analyzed to identify differentially expressed ATGs, followed by functional enrichment, immune cell profiling, and network analysis. Ten hub genes were validated in clinical samples (PCOS and controls, n = 6 per group) and a dehydroepiandrosterone-induced mouse model. HMOX1 function was examined under conditions with and without metformin treatment.
Results: A total of 57 DEATGs were enriched in pathways related to autophagy, immune regulation, and inflammation, including the NOD-like receptor and FoxO signaling pathways. Among the ten identified hub genes, heme oxygenase-1 (HMOX1) was significantly upregulated in PCOS samples and positively associated with M2 macrophage infiltration. In vitro, HMOX1 overexpression led to increased levels of p62 and CD163, indicating impaired autophagic flux and enhanced M2-like polarization. Estradiol secretion was reduced under HMOX1 overexpression, and partially restored by metformin. In the PCOS mouse model, HMOX1 expression was elevated and suppressed following metformin treatment, although ovarian morphology remained abnormal.
Conclusion: HMOX1…
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