Abstract

Hexavalent chromium [Cr(VI)] is a widespread environmental contaminant known to cause severe organ damage, with acute exposure leading to significant nephrotoxicity. To elucidate the underlying mechanisms, this study investigated the role of the mitophagy-ferroptosis axis in Cr(VI)-induced renal injury using mouse models and renal tubular epithelial cells (mRTECs). We found that Cr(VI) exposure disrupted mitochondrial iron homeostasis in mRTECs, leading to Mito-Fe 2+ accumulation and mitochondrial damage. Consequently, this triggered an overproduction of mitochondrial and total reactive oxygen species (Mito-ROS/total ROS) and initiated lipid peroxidation. Furthermore, our mechanistic studies revealed that Cr(VI) induced FUNDC1-dependent mitophagy, which specifically targeted the degradation of SLC7A11. This event downregulated GPX4 and impaired the glutathione antioxidant system, thereby exacerbating lipid peroxidation and ultimately driving ferroptosis. In vivo studies corroborated these findings, demonstrating evident renal injury in Cr(VI)-exposed mouse. Collectively, Our data reveal a novel mechanism whereby FUNDC1-mediated mitophagy participates in hexavalent Cr(VI)-induced renal ferroptosis through degradation of SLC7A11. These results not only clarify a key pathological pathway but also highlight the therapeutic potential of targeting the SLC7A11-FUNDC1 axis to mitigate Cr(VI) nephrotoxicity.