Wuling powder alleviates acute kidney injury by regulating S1PR2/GPX4 axis to inhibit ferroptosis.

BACKGROUND: Acute kidney injury (AKI) is a critical clinical syndrome with limited curative therapies. Tubular epithelial cell death is a central event in AKI progression in which ferroptosis plays a pivotal role. Pharmacological inhibition of ferroptosis attenuates renal inflammation and preserves kidney function, positioning it as a promising therapeutic strategy for AKI. Wuling powder (WLS) is a classic formula used for kidney diseases; however, whether it confers renoprotection by modulating ferroptosis in AKI remains unclear. PURPOSE: To investigate whether WLS attenuates cisplatin-induced AKI by inhibiting ferroptosis and to elucidate the underlying mechanism. METHODS: AKI models were established in mice and mouse renal tubular epithelial cells using cisplatin. Renal function, histopathology, inflammatory responses, and ferroptosis-related markers were assessed. Potential targets were screened, and the regulatory mechanism was defined. Renal tubule-specific S1pr2 knockout mice were generated to validate the functional role of the identified pathway. RESULTS: WLS treatment significantly attenuated cisplatin-induced AKI, as evidenced by improved renal function and histology, suppressed inflammation, and inhibited ferroptosis. Mechanistically, WLS upregulated S1P levels, activated the S1PR2/GPX4 axis, and promoted their interaction. Tubule-specific S1pr2 deletion exacerbated renal injury and ferroptosis, and largely abolished the renoprotective effects of WLS. CONCLUSION: WLS alleviates cisplatin-induced AKI by activating the S1PR2/GPX4 axis, thereby inhibiting ferroptosis, reducing inflammation, and improving renal function. These findings reveal a novel mechanism of WLS and identify the S1PR2/GPX4 axis as a promising therapeutic target for AKI.