PM2.5-induced ferroptosis via the miR-188-3p/GPX4 axis disrupts renal erythropoietin production.

Exposure to fine particulate matter (PM2.5) is a significant environmental risk factor for renal pathologies, including chronic kidney disease and acute kidney injury. Ferroptosis is increasingly implicated in kidney pathology or PM2.5-induced toxicology. However, the direct mechanistic link between PM2.5 and renal ferroptosis, particularly within an endocrine context, remains elusive. In this study, pathological injury, kidney fibrosis, lipid peroxidation (LPO), iron ions, and ferroptosis effects were measured in in vivo and in vitro experiments following PM2.5 exposure. Ferroptosis was visualized by confocal microscopy of glutathione (GSH)/reactive oxygen species (ROS). Next, the glutathione peroxidase-4 (GPX-4) function and its regulation by miR-188-3p were verified. EPO and aldosterone levels were also measured. Results showed that PM2.5 exposure induced renal pathological injury and fibrosis, along with the abnormal changes in the levels of related factors (IL-6, TNF-α, Fibronection, Col4A2, TGF-β, and KIM-1). At the same time, PM2.5 caused ferroptosis, as evidenced by iron overload, elevated ROS and LPO, reduced GSH levels, and dysregulation of ferroptosis-related proteins (GPX-4 and Acsl4). The critical role of GPX-4 was confirmed by the ferroptosis inhibitor ferrostatin-1, which attenuated these injurious effects. The miR-188-3p mimic and inhibitor experiments validated miR-188-3p regulation of GPX-4. Of note, PM2.5 significantly reduced EPO levels compared with controls and was linked to ferroptosis. Our findings elucidate a novel miR-188-3p/GPX-4/ferroptosis pathway of PM2.5-induced kidney injury, accompanied by renal EPO endocrine disruption. These also reveal potential therapeutic targets for combating air pollution-related kidney diseases.