Integrated stress response inhibition decouples cardiotoxicity from anthracycline chemotherapy while enhancing antitumor efficacy.

The clinical efficacy of anthracycline chemotherapeutics is severely limited by their dose-dependent cardiotoxicity, a condition lacking effective preventive strategies. We identify the maladaptive ATF4-dependent integrated stress response (ISR) program as a central driver of this pathology. In murine models, ISR inhibition achieved by either cardiomyocyte-specific knockout of the transcription factor ATF4 or the ISR inhibitor (ISRIB), provides robust protection from doxorubicin (DOX)-induced cardiac dysfunction, remodeling, and injury. Mechanistically, we delineate a regulatory pathway in which DOX-activated ATF4 directly upregulates the methyltransferase METTL1. This ATF4-METTL1 axis promotes N7-methylguanosine (m7G) methylation of NLRP3 mRNA, thereby triggering NLRP3 inflammasome activation, mitochondrial damage, and cardiomyocyte pyroptosis. Crucially, pharmacological ISR inhibition with ISRIB synergizes with DOX to enhance tumor regression in xenograft models without causing cardiac injury. These findings establish the ISR as a therapeutically actionable target to simultaneously prevent anthracycline-induced cardiotoxicity and enhance chemotherapeutic efficacy, offering a promising strategy to refine cancer treatment.