Cadmium-mediated autophagy increases ferroptosis of ovarian granulosa cells

Abstract

Cadmium (Cd) is a pervasive environmental toxicant that poses significant threats to female reproductive health. Accumulating evidence has linked Cd exposure to ovarian dysfunction and infertility. As critical somatic components of ovarian follicles, granulosa cells (GCs) regulate folliculogenesis and oocyte maturation, and their dysfunction is implicated in various reproductive disorders including premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS). However, the precise mechanisms underlying Cd-induced GC injury are not yet fully understood. Here, we demonstrate that Cd exposure triggers GC death via ferroptosis, an iron-dependent form of regulated cell death characterized by uncontrolled lipid peroxidation. Mechanistically, Cd induces mitochondrial dysfunction and glutathione peroxidase 4 (GPX4) downregulation, leading to reactive oxygen species (ROS) accumulation and subsequent oxidative damage. Intriguingly, we identified autophagy activation as a key regulator of Cd-triggered ferroptosis, evidenced by increased LC3-II conversion and autophagic flux. Importantly, the protective effect of chloroquine (Cq) against Cd-induced cell death provides compelling evidence for the essential role of autophagic activation in mediating Cd-triggered ferroptosis. Our findings not only elucidate a novel molecular pathway connecting Cd exposure to female infertility but also provide preclinical evidence for targeting the autophagy-ferroptosis axis in reproductive toxicology.