Salvigenin alleviates diabetic nephropathy through Nrf2-mediated modulation of renal inflammation and ferroptosis.

BACKGROUND: Diabetic nephropathy (DN) is a leading cause of global end-stage renal disease, driven by oxidative stress, persistent inflammation and ferroptosis. Salvigenin, a natural flavonoid with anti-inflammatory and antioxidant activity, displays protective effects against oxidative injury. This study investigated its renoprotective actions in DN and the underlying mechanism. METHODS: In vitro high glucose-stimulated HK-2 cell model and in vivo db/db DN mouse model were adopted. HK-2 cells were treated with gradient salvigenin for 24 h. We assessed cell viability, proliferation, inflammatory cytokines, iron and ROS levels, antioxidant status, and expression of Nrf2 pathway proteins. DN mice received intraperitoneal salvigenin every other day for 8 weeks. Renal function, histopathology, inflammation, iron deposition, ROS accumulation and Nrf2 signaling activity were comprehensively evaluated. RESULTS: In vitro, salvigenin reversed high glucose-induced cytotoxicity and proliferative suppression. It lowered pro-inflammatory cytokine release, relieved iron overload and ROS accumulation, restored GSH, and reduced MDA and 4-HNE. Salvigenin upregulated ferroptosis mediators GPX4 and SLC7A11 and activated the Nrf2/NQO-1 pathway. In vivo, consistent with cellular data, salvigenin improved renal function, alleviated pathological lesions, suppressed inflammation and iron deposition, and enhanced Nrf2 signaling in DN mice. CONCLUSION: This study confirms salvigenin confers potent renoprotection against DN. Mechanistically, salvigenin activates the Nrf2 cascade to strengthen antioxidant defense, alleviate oxidative and inflammatory injury, and inhibit renal tubular ferroptosis. These results uncover the molecular mechanism of salvigenin and offer experimental support for developing natural flavonoids as candidate agents for DN treatment.