Cadmium (Cd) is a ubiquitous environmental pollutant, and the ovarian fibrosis it induces represents both a critical trigger and a pathological hallmark of female reproductive aging; however, the underlying mechanisms and effective interventions remain poorly defined. The present study demonstrates that dietary selenium (Se) alleviates Cd-induced ovarian fibrosis in chickens. In vivo macrophage depletion experiments revealed that macrophages serve as the key cellular mediators of both Cd-induced ovarian toxicity and the protective effects of Se. In vitro studies showed that Cd induces ferroptotic stress in macrophages, characterized by Fe²⁺ overload and the accumulation of lipid peroxides, which in turn activates the DNA damage response and contributes to cellular senescence. The ferroptosis inhibitor ferrostatin-1 (Fer-1) recapitulated the anti-senescence effects of Se, supporting that ferroptotic stress contributes to macrophage senescence. Transwell co-culture assays further demonstrated that Cd-treated senescent macrophages promoted fibroblast activation, accompanied by increased paracrine secretion of senescence-associated secretory phenotype (SASP) factors, including TGF-β1 and IL-6. Mechanistically, Se restored GPX4 activity and reduced lipid peroxidation, thereby suppressing ferroptotic stress-associated macrophage senescence and SASP secretion; GPX4 knockdown experiments further supported the involvement of GPX4 in these protective effects. Together, these findings indicate that Se mitigates Cd-induced ovarian fibrosis and suggest that GPX4 contributes to its protective effects against ferroptotic stress and macrophage senescence, providing a novel theoretical basis for understanding ovarian fibrosis and reproductive impairment caused by environmental heavy metal exposure.
