Hesperetin ameliorates mitochondrial dysfunction in acute kidney injury by mediating autophagy and inhibiting the cGAS-STING pathway.

Cisplatin-induced acute kidney injury (AKI) represents a severe complication of anticancer therapy with no effective clinical interventions, frequently necessitating chemotherapy dose reduction or discontinuation. Natural products have emerged as promising therapeutic candidates against cisplatin nephrotoxicity due to their multi-target mechanisms, pleiotropic effects, and low resistance potential. This study explored the therapeutic potential of hesperetin (Hes) in ameliorating mitochondrial dysfunction during AKI through coordinated induction of autophagy and suppression of the cGAS-STING pathway. We established an HK-2 cell injury model through cisplatin exposure. Following Hes intervention, cell viability was quantified via CCK-8 assays, apoptosis assessed by Annexin V-FITC/PI staining, and mitochondrial function evaluated through ATP production measurement, mitochondrial reactive oxygen species (ROS) detection and mitochondrial membrane potential analysis employing JC-1 staining. For in vivo validation, C57BL/6 mice developed AKI following single intraperitoneal cisplatin administration. Renal function parameters were determined through serum biochemistry, while renal histopathology was examined using periodic acid-Schiff (PAS) staining. Protein expression changes in mitochondrial autophagy markers and cGAS-STING pathway components were subsequently analyzed through immunofluorescence and Western blotting techniques. Autophagy modulators were employed to elucidate the precise mechanisms through which autophagy mediates Hes's protective effects against cisplatin-induced AKI. In vitro, Hes intervention effectively reversed cisplatin-induced HK-2 cell injury and mitochondrial dysfunction while enhancing mitochondrial autophagy. Notably, the autophagy activator rapamycin alone, or co-administered with Hes produced comparable cytoprotective effects to Hes. Conversely, the autophagy inhibitor 3-methyladenine exacerbated cellular damage and partially attenuated Hes-mediated protection. In vivo studies confirmed Hes significantly ameliorated AKI through improved renal function and histopathology, concurrently reducing mitochondrial ROS levels while promoting autophagic clearance. Furthermore, Hes treatment potently suppressed activation of the cGAS-STING pathway in both experimental models. Hes ameliorates mitochondrial dysfunction in AKI by enhancing mitochondrial autophagy and inhibiting the cGAS-STING pathway.