Rosmarinic Acid Alleviates Cisplatin-Induced Acute Kidney Injury by Targeting FYN to Regulate Ferroptosis

Cisplatin (CDDP) is a widely used chemotherapeutic agent, but its nephrotoxic side effects limit its clinical application, which can lead to severe acute kidney injury (AKI). Growing evidence indicates that ferroptosis plays a critical role in CDDP-AKI. Rosmarinic acid (RA) is a natural polyphenolic compound extracted from various plants that has been demonstrated to possess significant antioxidant and anti-inflammatory activities. This study aims to investigate whether RA protects against CDDP-AKI by regulating ferroptosis. We demonstrated that RA significantly ameliorated renal dysfunction, pathological damage, and inflammatory responses in CDDP-AKI mice. Furthermore, RA effectively suppressed ferroptosis by regulating the Nrf2/HO-1 signaling axis, as evidenced by reduced lipid peroxidation levels and restored expression of key ferroptosis-related proteins (GPX4 and xCT). Integrating network pharmacology predictions with molecular docking, we identified FYN as a potential direct target of RA and further verified that RA inhibits the expression and activation of FYN. Additionally, pharmacological inhibition of FYN using Saracatinib in vivo or genetic knockdown of FYN in HK-2 cells effectively alleviated CDDP-induced renal tubular injury and lipid metabolic dysregulation. In conclusion, our findings indicate that RA alleviates CDDP-AKI by targeting FYN to regulate the ferroptosis pathway, highlighting that RA is a promising candidate for preventing and treating CDDP-AKI.