Licochalcone A protects against cisplatin-induced acute kidney injury via the modulation of Nrf2/Keap1-mediated ferroptosis and apoptosis.

BACKGROUND

The use of cisplatin (CP), a widely used chemotherapeutic agent, is severely limited by the high incidence of CP-induced acute kidney injury (AKI). Licochalcone A (Lico A) is a natural chalcone isolated from Glycyrrhiza inflata that has multiple beneficial effects, but its potential role in CP-induced AKI through apoptosis and ferroptosis remains unclear.

PURPOSE: To investigate the therapeutic effects of Lico A on CP-induced AKI and clarify the underlying molecular mechanisms.

MATERIALS AND

METHODS

In vivo and in vitro models of CP-induced AKI were established using male C57BL/6 mice and human renal proximal tubular epithelial HK2 cells, respectively, to systematically evaluate the renoprotective effects of Lico A. Renal function parameters and kidney injury biomarkers were measured in the mice. Mitochondrial function, oxidative stress, lipid peroxidation, and key indices related to apoptosis and ferroptosis were also assessed.

RESULTS

Lico A treatment significantly ameliorated CP-induced AKI, accompanied by reduced serum levels of urea nitrogen and creatinine, downregulated expression of kidney injury molecule-1 and neutrophil-gelatinase-associated lipocalin, and attenuated renal histopathological damage. In vivo and in vitro, Lico A reduced CP-triggered renal apoptosis and the expression of apoptosis-related proteins. Additionally, Lico A mitigated ferroptosis by suppressing iron overload, oxidative stress, lipid peroxidation and mitochondrial dysfunction. Lico A also markedly activated nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling. Notably, pharmacological inhibition of Nrf2 with ML385 abolished the renoprotective effect of Lico A, as well as its suppression of apoptosis and ferroptosis.

CONCLUSION

This study demonstrated that Lico A exerts significant renoprotective effects against CP-induced AKI. The underlying renoprotective mechanism involves activation of the Nrf2/Keap1 pathway, which in turn inhibits apoptosis and ferroptosis in renal tubular epithelial cells. Lico A therefore shows promise as a potential therapeutic candidate for the prevention and treatment of CP chemotherapy-associated kidney injury.