Interconnected cell death pathways: central mechanisms and therapeutic targets in impaired follicular development of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance, which synergistically disrupt the ovarian microenvironment. This pathological interplay induces chronic inflammation, oxidative stress, and metabolic dysregulation, subsequently triggering aberrant activation of multiple forms of programmed cell death (PCD) in granulosa cells, including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis. Recent experimental studies, mainly based on animal and in vitro models, suggest that these death pathways may be interconnected through shared regulatory hubs, forming a dynamic interactive network referred to as the ‘death crosstalk’. Inhibition of apoptosis leads to defective follicular atresia and accumulation of immature follicles; pyroptosis and necroptosis amplify inflammatory cascades, promoting ovarian fibrosis and aggravating insulin resistance; ferroptosis induces lipid peroxidation–mediated granulosa cell injury, thereby reducing follicle-stimulating hormone (FSH) sensitivity; dysregulated autophagy exacerbates ferroptosis through ferritinophagy and degradation of GPX4. Targeting key nodes of the death crosstalk network—such as the NLRP3 inflammasome, RIPK1/RIPK3, and the ferroptosis–GPX4 axis—or employing epigenetic and gene-editing interventions, potentially holds promise for overcoming the limitations of single-target therapies. Such multi-target modulation may provide novel strategies to simultaneously improve ovulatory dysfunction and metabolic complications in PCOS.