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

WLS attenuates cisplatin-induced AKI by ameliorating renal dysfunction, suppressing inflammation, and inhibiting ferroptosis. • Mechanistically, WLS upregulates S1P levels, activates the S1PR2/GPX4 axis, and promotes the interaction between S1PR2 and GPX4. • Tubule-specific deletion of S1pr2 markedly attenuates the renoprotective and anti-ferroptosis effects of WLS, exacerbating AKI, underscoring S1PR2 as a critical therapeutic target. 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. Download: Download high-res image (194KB) Download: Download full-size image