The crosslink between autophagy and ferroptosis in polycystic ovary syndrome: from synergistic pathogenesis to targeted therapy.

Polycystic ovary syndrome (PCOS) is a highly heterogeneous endocrine-metabolic disorder whose core pathological features-follicular atresia and ovulatory dysfunction-are attributed to functional failure of ovarian granulosa cells (GCs). Although autophagy (a cellular quality-control mechanism) and ferroptosis (iron-dependent lipid peroxidation-driven cell death) have been shown to independently contribute to the pathophysiology of PCOS, their interactive networks and regulatory mechanisms within specific pathological microenvironments remain to be systematically elucidated. This review aims to systematically unravel this overlooked micro-pathogenic network. The dysfunction of GCs in PCOS is not an isolated event involving a single mode of cell death, but rather a pathological crosstalk arising from the disruption of the dynamic equilibrium between autophagy and ferroptosis. This paper elucidates the pathological mechanisms driving this cascade of disturbances through four distinct pathways: the intracellular stress hub formed by the synergistic action of oxidative stress (OS) and endoplasmic reticulum stress (ERS) serves as the initiating factor. This is compounded by the gut-ovarian axis's long-range amplification effect, mediated by gut microbiome (GM) dysregulation and low-grade chronic inflammation (LGI), collectively disrupting cellular homeostasis. while circadian rhythm disruption and epigenetic reprogramming, respectively, cement this imbalance at the temporal and molecular memory levels. Moreover, we have elucidated the specific execution pathways of autophagy-dependent ferroptosis, namely how selective autophagy (e.g., ferritinophagy and mitophagy) acts as a key amplifier of ferroptosis by exacerbating iron overload and energy collapse. On this basis, this paper explores therapeutic strategies ranging from upstream restoration of signal homeostasis to downstream precise inhibition of autophagy-ferroptosis interaction nodes. This review aims to provide novel theoretical perspectives for fundamentally reversing follicular atresia in PCOS and improving patients' reproductive outcomes by re-examining these lethal interactions at the microscopic level.