Association of F-53B Nephrotoxicity with Oxidative Stress-Mediated Mitochondrial Dysfunction and Altered Autophagy–Apoptosis Crosstalk

6:2 chlorinated polyfluorinated ether sulfonate (F-53B, also known as 6:2 Cl-PFESA) is a major alternative to perfluorooctane sulfonate (PFOS) and a widespread environmental pollutant with potential public health hazards. However, its nephrotoxic effects and underlying molecular mechanisms remain poorly understood. This study investigated renal injury induced by environmentally relevant concentrations of F-53B and delineated the mechanistic cascade using a mouse model combined with quantitative proteomic and molecular biological approaches. Male C57BL/6 mice were exposed to 0, 4, 40, and 400 μg/L F-53B for 4 weeks. F-53B exposure led to significant renal dysfunction, histopathological damage, elevated renal injury biomarkers, and pronounced oxidative stress in a dose-dependent manner. A proteomic comparison of the 0 μg/L versus 400 μg/L groups identified 276 differentially expressed proteins that were strongly enriched in oxidative phosphorylation, autophagy, and apoptosis pathways, with cytochrome c oxidase subunit 7b (Cox7b) serving as a core downregulated hub molecule. Further validation confirmed that F-53B triggered overt mitochondrial structural damage, impaired respiratory chain complex assembly, aberrant ATP production, and disturbed mitochondrial dynamics. Consequently, excessive autophagy activation and mitochondrial-mediated apoptosis were simultaneously stimulated in renal tissues. Notably, although statistically significant, the alterations induced by F-53B were generally mild in magnitude. Collectively, our findings demonstrate that F-53B induces nephrotoxicity through a sequential pathological cascade. This study provides novel mechanistic insights into F-53B-elicited renal injury and highlights the potential health risks of this emerging per- and polyfluoroalkyl substance (PFAS) alternative.