RNAi-mediated p38δ silencing mitigates anthracycline cardiotoxicity in female mice

The anthracycline antibiotic doxorubicin (DOX) is a potent chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity. We previously reported that genetic deletion of p38δ protects female mice from DOX-induced cardiotoxicity (DIC), suggesting that inhibiting this kinase could be an effective treatment. Here, we developed a fully chemically stabilized small interfering RNA (siRNA) that effectively silences p38δ. In an acute DIC model, silencing p38δ reduced mortality and morbidity, preserved heart structure and function, and decreased fibrosis in female mice. It also alleviated DOX-induced electrophysiological remodeling and decreased cardiac inflammation and senescence-associated secretory phenotype (SASP). Transcriptomic analysis of DOX-treated p38δ-deficient hearts revealed the downregulation of genes associated with inflammation, ion transport, and impulse generation, and the upregulation of genes involved in oxidative stress management, autophagy, and immune signaling. These findings support silencing p38δ as a promising approach to protect against DIC, highlighting the potential of siRNA-based therapies to mitigate anthracycline cardiotoxicity. NEW & NOTEWORTHY This study presents the first isoform-specific inhibition of p38δ using a docosanoic (DCA)-conjugated, fully chemically stabilized siRNA. Our lead compound, si644, achieves potent, durable, and well-tolerated p38δ silencing in vivo in mouse hearts and ex vivo in human cardiac organotypic slices. si644-mediated p38δ silencing protects female mice from DIC by mitigating DOX-induced structural, electrophysiological, fibrotic, and inflammatory remodeling. These findings establish p38δ inhibition as a promising therapeutic strategy for preventing anthracycline cardiotoxicity.