HIF1α Attenuates Doxorubicin-Induced Cardiotoxicity by Activating TEX264-Associated ER-phagy

The clinical utility of doxorubicin, a potent chemotherapeutic agent, is severely limited by its dose-dependent cardiotoxicity. Hypoxia-inducible factor 1α (HIF1α) is a key regulator of cardiovascular adaptation, but its role and mechanism in doxorubicin-induced cardiotoxicity (DIC) remain unclear.

Using in vitro (AC16 cells) and in vivo (mouse) models of DIC, we used genetic (knockout, knockdown) and pharmacological (FG4592) approaches to modulate HIF1α. Cardiac function, apoptosis, endoplasmic reticulum (ER) morphology, and ER-phagy flux were assessed. Molecular mechanisms were investigated using chromatin immunoprecipitation and promoter activity assays.

HIF1α exhibited a dynamic, biphasic expression pattern during DIC progression. Stabilization of HIF1α by FG4592 alleviated doxorubicin-induced cardiac dysfunction, atrophy, fibrosis, and apoptosis, whereas HIF1α knockout exacerbated these injuries. The protective effects of FG4592 were strictly dependent on HIF1α. Mechanistically, HIF1α transcriptionally activated the ER-phagy receptor gene testis-expressed protein 264 (TEX264) by directly binding to its promoter. This activation enhanced ER-phagy, and suppressed ER stress-mediated apoptosis. Crucially, ablation of TEX264 abolished the cardioprotective effects of both HIF1α and FG4592.

This study identifies a novel HIF1α/TEX264/ER-phagy axis that is suppressed in DIC and is central to cardiomyocyte survival. Targeting this pathway, particularly with the clinically available HIF1α stabilizer FG4592, represents a promising therapeutic strategy against DIC.