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

TL;DR

This study shows that Mulberrin protects against kidney injury by reducing cell death and oxidative stress through activation of Sirt3.

Contribution

The study identifies a novel mechanism by which Mulberrin alleviates renal I/R injury via Sirt3 activation and suppression of ferroptosis.

Findings

Mulberrin improves renal function and reduces tubular injury in IRI mice.

Mulberrin suppresses ferroptosis by restoring GSH levels and decreasing oxidative stress markers.

Sirt3 activation is essential for the protective effects of Mulberrin against renal injury.

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

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