Carvedilol, an antihypertensive drug that reduces morbidity and mortality in heart failure, alleviates ferroptotic damage in cardiomyocytes and hepatocytes.

Oxidative stress-driven ferroptosis plays particularly important role in ischemia/reperfusion-associated myocardial injury and toxicant-induced liver injury. Carvedilol, a widely-prescribed antihypertensive agent with proven survival benefits in chronic heart failure patients, was evaluated in this study for its antiferroptotic activity. Using H9C2 rat cardiomyocytes and BRL-3A rat hepatocytes as in vitro models, we examined whether carvedilol can effectively alleviate chemically-induced ferroptotic injuries. We found that carvedilol afforded robust cytoprotection against ferroptosis triggered by multiple canonical inducers, including RSL3, erastin, glutamate, sulfasalazine and l-buthionine-(S,R)-sulfoximine. The cytoprotective effect of carvedilol was accompanied by decreased cellular levels of nitric oxide, reactive oxygen species and lipid peroxidation. Mechanistic studies indicate that carvedilol can directly bind to protein disulfide isomerase (PDI) and attenuate its oxidase activity, thereby restraining PDI-mediated dimerization and activation of nitric oxide synthase, reducing nitric oxide accumulation and downstream oxidative stress. Consistent with these cell-based findings, carvedilol mitigated acetaminophen-induced, glutathione depletion-associated oxidative liver injury in mice. Together, these results clearly identify PDI as a key pharmacological target of carvedilol, and link PDI oxidase inhibition to the protection against oxidative ferroptosis in multiple test systems, thereby providing a mechanistic basis for its organ protective clinical profiles.