Chromatin remodeling factor CHRAC1 regulates doxorubicin-induced cardiotoxicity via IRF9/GSDMD/CASP-1

Doxorubicin-induced cardiotoxicity (DIC) is a severe complication of cancer therapy, yet the contribution of epigenetic regulators remains largely unknown. In this study, we identify the chromatin remodeler CHRAC1 as a novel determinant of DIC. Using murine and cellular models, we observed that CHRAC1 knockdown significantly preserved cardiac function, improved cell viability, and reduced reactive oxygen species accumulation and cardiomyocyte death. In contrast, CHRAC1 overexpression aggravated cardiac injury and enhanced cell death. Integrated RNA-seq and ATAC-seq analyses revealed that CHRAC1 transcriptionally activates the NOD-like receptor signaling pathway, with IRF9 identified as a critical downstream mediator. Silencing IRF9 reversed CHRAC1-driven pathological phenotypes, thereby establishing a functional connection between CHRAC1 and the IRF9/GSDMD/CASP-1 axis. These findings demonstrate that CHRAC1 promotes caspase-1-dependent pyroptosis through transcriptional regulation of IRF9, highlighting a previously unrecognized epigenetic-immune signaling network. Collectively, our work uncovers the CHRAC1-IRF9-pyroptosis axis as a promising therapeutic target for preventing and treating anthracycline cardiotoxicity.