Pharmacological activation of HSF1 by HSF1A mitigates heatstroke-induced acute kidney injury via ferroptosis inhibition.

Abstract

Heatstroke-induced acute kidney injury (HS-AKI) is a serious clinical complication, with ferroptosis implicated in its pathogenesis. While heat shock factor 1 (HSF1) is a known regulator of ferroptosis, its role in HS-AKI remains unclear. Here, we demonstrated that heatstroke triggered ferroptosis-associated renal damage in mice, characterized by elevated serum creatinine, blood urea nitrogen, and tissue iron deposition, alongside transcriptomic signatures of ferroptosis and HSF1 pathway activation. Notably, HSF1 expression was transiently activated by heat stress, and simultaneously promoted the expression of heat shock proteins (HSPs), but decreased in the late phase of heat shock. Knockdown of HSF1 in renal tubular cells exacerbated HS-induced ferroptotic death. Conversely, renal-specific overexpression of HSF1 rescued heatstroke-caused deleterious phenotype in mice. Importantly, pharmacological activation of HSF1 by HSF1A attenuated oxidative stress, rectified iron dyshomeostasis, inhibited lipid peroxidation, and conferred significant protection against HS-AKI. These results identify HSF1 activation as an endogenous adaptive response that limits ferroptosis during heatstroke, positioning HSF1A as a promising therapeutic candidate for HS-AKI.