Key result
Calpain-1 knockdown mitigates doxorubicin-induced myocardial damage and ferroptosis by inhibiting p53 stabilization.
Why the study?
The molecular mechanism linking Calpain-1 to cardiomyocyte ferroptosis in doxorubicin-induced cardiotoxicity remains poorly clarified.
Does Calpain-1 knockdown prevent doxorubicin-induced cardiotoxicity and ferroptosis in preclinical models?
Does Calpain-1 knockdown prevent doxorubicin-induced cardiotoxicity and ferroptosis in preclinical models?
Calpain-1 knockdown protects against doxorubicin-induced cardiotoxicity by preventing p53-mediated cardiomyocyte ferroptosis, identifying a potential therapeutic target.
Calpain-1 inhibition may mitigate DIC in vitro; leaves open in vivo efficacy and clinical translation.
Doxorubicin (Dox), a widely applied anthracycline antitumor agent, exhibits severe dose-dependent cardiotoxicity that greatly restricts its clinical utilization, yet the molecular mechanism linking Calpain-1 to cardiomyocyte ferroptosis in doxorubicin-induced cardiotoxicity (DIC) remains poorly clarified. This study aimed to explore how Calpain-1 regulates cardiomyocyte ferroptosis in DIC. Differentially expressed proteins from Dox-treated H9c2 cells were screened by proteomics, stable Calpain-1 knockdown cell lines were generated to detect cell viability and ferroptosis indicators through CCK-8, FerroOrange staining, biochemical kits and western blotting, and PPI network, co-IP and cycloheximide chase assays were performed to confirm Calpain-1 - p53 binding and p53 protein stability regulation, with p53 rescue tests further verifying their functional relationship. In vivo, Calpain-1 expression was detected in Dox - exposed mouse hearts, and AAV9-driven myocardial Calpain-1 knockdown was established in DIC mice, where myocardial injury and ferroptosis were evaluated by HE staining, serum CK-MB/LDH and protein detection. Calpain-1 was significantly upregulated in Dox - stimulated cardiomyocytes and cardiac tissue. Calpain-1 silencing alleviated Dox - induced ferroptosis in vitro, with decreased Fe 2+ , MDA, LPO and ACSL4, elevated GSH and SLC7A11; co-IP verified direct Calpain-1 - p53 interaction, and cycloheximide assays proved Calpain-1 inhibits p53 degradation to accumulate p53 protein, whereas p53 overexpression completely abolished the protective effect of Calpain-1 knockdown. Consistent with cellular results, cardiac-specific Calpain-1 knockdown mitigated myocardial damage and suppressed ferroptosis in DIC mice. These findings suggest that Calpain-1 exacerbates DIC by stabilizing p53 to initiate p53-dependent cardiomyocyte ferroptosis, offering a novel therapeutic target and theoretical basis for DIC intervention.
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Zhang et al. (2026) studied Doxorubicin-induced cardiotoxicity. Calpain-1 knockdown vs. Doxorubicin-exposed controls was evaluated on Myocardial injury and ferroptosis. Calpain-1 knockdown mitigated doxorubicin-induced myocardial damage and suppressed ferroptosis in vitro and in vivo by inhibiting p53 stabilization.
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