Hspa1b attenuates hypoxia/reoxygenation-induced cardiomyocyte injury through dual suppression of P53-driven apoptotic and ferroptotic pathways

  • Cell Stress Chaperones. 2026 Jun 24;31(4):100194. doi: 10.1016/j.cstres.2026.100194.
Chang Liu  1 ,  Wensheng Qi  1 ,  Yue Li  1 ,  Tingting Fan  2 ,  Yun Lan  3 ,  Lei Pang  1 ,  Haichun Ma  4 ,  Yin Cai  5
Affiliations
  • 1. Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China.
  • 2. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 3. HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
  • 4. Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China. Electronic address: [email protected].
  • 5. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; Research Institute of Smart Ageing, The Hong Kong Polytechnic University, Hong Kong SAR, China; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China. Electronic address: [email protected].
PMID: 42342026 DOI: 10.1016/j.cstres.2026.100194
Abstract

While the cardioprotective role of heat shock proteins (HSPs) in cardiovascular diseases is well established, the isoform-specific functions of HSP70 members in ischemia-reperfusion (I/R) injury remain unclear. This study investigates the role of Hspa1b, a stress-inducible HSP70 isoform, in cardiac I/R injury and elucidates its underlying mechanisms. In vivo, male C57BL/6 J mice were subjected to myocardial I/R surgery. In vitro, H9C2 cardiomyocytes were transfected with siRNA targeting Hspa1b or p53 and subjected to a hypoxia/reoxygenation (H/R) model. Cellular injury was quantified via Lactate Dehydrogenase (LDH) release, while viability was assessed using the CCK-8 assay. Apoptotic (Bax, Bcl2, and cleaved Caspase3) and ferroptotic (GPX4, XCT/SLC7A11) markers were analyzed by Western blotting. We found that I/R injury in mouse hearts upregulated Hspa1b and p53 protein levels, accompanied by increased infarct size and elevated plasma CK-MB levels. Similarly, H/R treatment in H9C2 cells increased Hspa1b and p53, which coincided with increased Apoptosis and Ferroptosis. Knockdown of Hspa1b exacerbated H/R-induced cellular injury, as evidenced by further increases in LDH release and reductions in cell viability, and amplified the changes in apoptotic and ferroptotic markers. Crucially, co-silencing Hspa1b and p53 partially rescued these effects, restoring cell viability and suppressing death pathways. Hspa1b confers cardioprotection against H/R injury by suppressing p53-mediated Apoptosis and Ferroptosis. These findings identify Hspa1b as a key protective regulator that mitigates I/R injury through dual regulation of cell death pathways.

Keywords
Apoptosis; Ferroptosis; Hspa1b; Hypoxia/reoxygenation; p53.
Products