Inhibition of HO-1 alleviates cardiac fibrosis by improving ferroptosis-mediated aberrant autophagy
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Updated: May 13, 2026
Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts
Published on: February 23, 2024
Chengyu Kong1, Hanyu Liu2, Shuxia Jiang1
1Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Noncoding RNA, Institute for Frontier Medical Technology, College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, 201620, PR China.
Insights
Heme oxygenase-1 (HO-1) drives cardiac fibrosis by promoting ferroptosis and impairing autophagy. Inhibiting HO-1 may offer a therapeutic strategy for heart failure by restoring autophagic homeostasis and reducing fibrosis.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Pathophysiology
Background:
- Cardiac fibrosis is a key factor in heart failure, but its mechanisms are not fully understood.
- Heme oxygenase-1 (HO-1) is involved in cardiac injury, but its role in fibrosis and ferroptosis is unclear.
- Understanding the interplay between HO-1, ferroptosis, and autophagy is crucial for developing new therapies.
Purpose of the Study:
- To investigate the role of Heme oxygenase-1 (HO-1) in regulating ferroptosis and cardiac fibrosis.
- To elucidate the mechanism by which HO-1 influences autophagic flux in fibrotic conditions.
- To evaluate HO-1 inhibition as a potential therapeutic strategy for cardiac fibrosis.
Main Methods:
- Induction of myocardial infarction in a mouse model and stimulation of cardiac fibroblasts with TGF-β1.
- Assessment of ferroptosis markers, including iron accumulation, ROS generation, and lipid peroxidation.
- Evaluation of autophagic flux, lysosomal function, and HO-1 expression levels.
- Intervention with ferroptosis inhibitors and HO-1 modulators, with and without autophagy blockade.
Main Results:
- Ferroptosis was activated in fibrotic conditions, characterized by increased iron, ROS, and lipid peroxidation.
- Inhibition of ferroptosis ameliorated fibrotic responses and improved cardiac function.
- HO-1 was upregulated in fibrosis, promoting ferroptosis and autophagic dysfunction.
- HO-1 inhibition restored autophagic homeostasis and attenuated cardiac fibrosis, an effect dependent on autophagy.
Conclusions:
- HO-1 promotes cardiac fibrosis by inducing ferroptosis and disrupting autophagic homeostasis.
- HO-1 inhibition represents a promising therapeutic approach for mitigating cardiac fibrosis and heart failure.
- The antifibrotic effects of HO-1 suppression are mediated through the restoration of autophagic activity.
Abstract:
Cardiac fibrosis is a major pathological feature of cardiovascular diseases and a key driver of ventricular remodeling and heart failure, yet effective therapeutic strategies remain limited due to incomplete mechanistic understanding. Heme oxygenase-1 (HO-1), a key redox-regulating enzyme, has recently been implicated in cardiac injury. However, its role in cardiac fibrosis, particularly through the regulation of ferroptosis, remains poorly understood. This study systematically investigated the effects of HO-1-mediated ferroptosis on the progression of cardiac fibrosis. Myocardial infarction was induced by ligation of the left anterior descending coronary artery, and cardiac fibroblasts were stimulated with transforming growth factor-β1 (TGF-β1) to induce fibrosis. Ferroptosis was markedly activated, accompanied by increased ferrous iron (Fe2+) accumulation, enhanced reactive oxygen species (ROS) generation, and elevated levels of lipid peroxidation. Inhibition of ferroptosis significantly alleviated fibrotic responses and improved cardiac function. Mechanistically, ferroptosis suppression restored autophagic flux by correcting lysosomal abnormalities and normalizing LC3B and p62 accumulation. Furthermore, HO-1 was markedly upregulated in fibrotic conditions, promoting ferroptosis and myocardial fibrosis. Activation of HO-1 induced myocardial fibrosis by triggering ferroptosis-associated autophagic dysfunction, whereas HO-1 inhibition mitigated ferroptotic injury, restored autophagic homeostasis, and attenuated fibrosis. Blocking autophagy abolished the protective effects of HO-1 suppression, demonstrating that the antifibrotic role of HO-1-mediated ferroptosis is dependent on autophagic activity. These findings reveal a novel mechanism by which HO-1-mediated ferroptosis impairs autophagic homeostasis to drive cardiac fibrosis, highlighting HO-1 inhibition as a potential therapeutic strategy for attenuating cardiac fibrosis.
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