Mulberrin Alleviates Renal Ischemia–Reperfusion by Inhibiting Ferroptosis and Oxidative Stress Through Sirt3 Activation

<b>Background:</b> Renal ischemia-reperfusion (I/R) injury represents a principal etiologic factor in acute kidney injury (AKI), in which ferroptosis plays a critical role. Mulberrin (Mul), a prenylated flavonoid with antioxidative properties, has an as-yet undefined role in renal I/R injury. <b>Methods:</b> We established a mouse renal IRI model and an HK-2 H/R system. Renal function, histological injury, oxidative stress, ferroptosis markers, and mitochondrial function were assessed. The role of Sirtuin 3 (Sirt3) in Mul-mediated effects was further examined using siRNA knockdown in HK-2 cells. <b>Results:</b> The administration of Mul led to a marked improvement in renal function, lessened tubular injury, and reduced apoptosis in IRI mice. Mul also restored GSH levels, decreased MDA and Fe²⁺ accumulation, and normalized expression of ferroptosis-related proteins, thereby suppressing ferroptosis. In H/R-injured HK-2 cells, Mul restored mitochondrial membrane potential, increased ATP production, and reduced ROS accumulation. Mechanistically, Mul markedly upregulated Sirt3 expression, and silencing Sirt3 abolished its antioxidant and anti-ferroptosis effects, confirming the essential role of Sirt3 in Mul-mediated protection. <b>Conclusions:</b> Our findings underscore Mul's therapeutic promise in acute kidney injury and provide a mechanistic foundation for interventions directed at the Sirt3-ferroptosis pathway to safeguard renal function.