2. Academic Validation
  3. The autophagy receptor NDP52 recruits the E3 ligase ASB2 to mediate NOX4 degradation, suppressing cardiomyocyte ferroptosis and ameliorating heart failure

The autophagy receptor NDP52 recruits the E3 ligase ASB2 to mediate NOX4 degradation, suppressing cardiomyocyte ferroptosis and ameliorating heart failure

  • Free Radic Biol Med. 2026 Apr:247:378-392. doi: 10.1016/j.freeradbiomed.2026.02.014.
Shouguo Yang 1,  Jian Wu 2,  Xiaoyue Song 2,  Hong Jiang 2,  Yunzeng Zou 2,  Lei Zhang 3,  Junbo Ge 2
Affiliations

Affiliations

  • 1 Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, China.
  • 2 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China.
  • 3 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China. Electronic address: [email protected].
PMID: 41662915 DOI: 10.1016/j.freeradbiomed.2026.02.014
Abstract

Background: Heart failure (HF) is characterized by cardiomyocyte loss. While Ferroptosis driven by NOX4 contributes to HF, how Autophagy regulates NOX4 stability remains unclear.

Methods: Using in vitro (isoproterenol-induced) and in vivo (TAC-induced) HF models, we combined pharmacological and genetic approaches with co-IP and molecular docking to investigate the autophagy-NOX4 axis.

Results: We identified a novel pathway wherein Autophagy activation prompts the receptor NDP52 to bind NOX4 and recruit the E3 Ligase ASB2, mediating K48-linked ubiquitination and autophagic degradation of NOX4. This process suppressed Ferroptosis and ameliorated cardiomyocyte injury. The NOX4 Inhibitor GLX351322, alone or combined with the Autophagy activator metformin, conferred significant cardioprotection in vivo.

Conclusion: Our findings reveal the 'autophagy-NDP52-ASB2-NOX4' axis as a crucial mechanism coupling Autophagy to Ferroptosis in HF, highlighting its therapeutic potential.

Keywords

Autophagy; Ferroptosis; Heart failure; NADPH oxidase 4 (NOX4); NDP52/ASB2 axis.

Figures
Products
Inhibitors & Agonists
Other Products