HIF1α Attenuates Doxorubicin-Induced Cardiotoxicity by Activating TEX264-Associated ER-phagy.
Summary
In preclinical DIC models, stabilizing HIF1α (e.g., with FG4592) reduced systolic dysfunction, fibrosis, and apoptosis by transcriptionally activating the ER-phagy receptor TEX264, thereby enhancing ER-phagy flux. Loss of HIF1α abrogated protection, positioning the HIF1α–TEX264 axis as a central survival pathway and actionable target in doxorubicin cardiotoxicity.
Key Findings
- HIF1α stabilization with FG4592 alleviated doxorubicin-induced systolic dysfunction, fibrosis, and apoptosis in vivo.
- HIF1α directly activated transcription of TEX264, enhancing ER-phagy flux; protection was abolished by HIF1α knockout.
- A biphasic HIF1α expression pattern characterized DIC progression; targeting the HIF1α–TEX264 axis restored adaptive ER-phagy.
Clinical Implications
Suggests repurposing HIF1α stabilization (e.g., FG4592/roxadustat) to mitigate cardiotoxicity in patients receiving doxorubicin, warranting early-phase clinical trials with cardiac safety and efficacy endpoints.
Why It Matters
Identifies a druggable ER-phagy pathway for preventing anthracycline cardiotoxicity with a clinically available HIF1α stabilizer, offering immediate translational potential in cardio-oncology.
Limitations
- Preclinical models; absence of human clinical data
- Potential off-target and systemic effects of HIF1α stabilization not evaluated in cancer-treated patients
Future Directions
Conduct phase 1/2 trials testing HIF1α stabilization to prevent anthracycline cardiotoxicity, incorporate ER-phagy biomarkers (e.g., circulating TEX264 signatures), and assess oncologic safety.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- V - Preclinical mechanistic evidence from cellular and animal models
- Study Design
- OTHER