PPP1R3G Deletion Blocks RIPK1-Mediated Apoptosis and Necroptosis in Doxorubicin-Induced Cardiotoxicity

Cardiotoxicity is a major limitation of cancer chemotherapy, exemplified by doxorubicin (DOX), yet its underlying mechanisms remain incompletely defined. Here, we identify Protein Phosphatase 1 Regulatory Subunit 3G (PPP1R3G) as a critical amplifier of DOX-induced cardiotoxicity. We show that DOX activates both apoptosis and necroptosis in vitro. Mechanistically, DOX first induces p38-dependent inhibitory phosphorylation of receptor-interacting protein kinase 1 (RIPK1), providing a transient brake on cell death. PPP1R3G facilitates the removal of inhibitory phosphorylation, thereby permitting RIPK1 activation, oligomerization, and downstream apoptotic signaling. Activated RIPK1 further promotes mitochondrial DNA (mtDNA) release, which induces IFN-β-mediated ZBP1 expression and establishes a positive feedback loop that amplifies late-stage necroptosis. Genetic ablation of Ppp1r3g suppresses both apoptosis and necroptosis in cardiomyocytes, attenuates inflammatory cytokine production, and protects mice from DOX-induced cardiac injury and mortality. These findings delineate a PPP1R3G-RIPK1 axis that converts an early protective phosphorylation checkpoint into sustained death signaling and identify PPP1R3G as a potential therapeutic target for cardioprotection.