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

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Cancer Therapeutics

Background:

• Doxorubicin chemotherapy causes dose-dependent cardiotoxicity, limiting its clinical use.
• The role of Hypoxia-inducible factor 1α (HIF1α) in doxorubicin-induced cardiotoxicity (DIC) is not well understood.

Purpose of the Study:

• To investigate the role and mechanism of HIF1α in DIC.
• To explore the potential of modulating HIF1α as a therapeutic strategy for DIC.

Main Methods:

• Utilized in vitro (AC16 cells) and in vivo (mouse) models of DIC.
• Employed genetic (knockout, knockdown) and pharmacological (FG4592) approaches to modulate HIF1α.
• Assessed cardiac function, apoptosis, ER morphology, and ER-phagy flux; investigated molecular mechanisms via ChIP and promoter assays.

Main Results:

• HIF1α expression showed a biphasic pattern during DIC.
• FG4592-mediated HIF1α stabilization protected against doxorubicin-induced cardiac injury, while HIF1α knockout worsened it.
• HIF1α activated TEX264 transcription, enhancing ER-phagy and reducing apoptosis; TEX264 ablation negated HIF1α's protective effects.

Conclusions:

• Identified a novel HIF1α/TEX264/ER-phagy pathway critical for cardiomyocyte survival in DIC.
• Targeting this pathway, using HIF1α stabilizers like FG4592, presents a promising therapeutic approach for DIC.