PPP1R3G–RIPK1–ZBP1 axis activates early-stage apoptosis and late-stage necroptosis to promote doxorubicin-induced cardiotoxicity

in mice significantly suppresses both apoptosis and necroptosis, attenuates systemic inflammatory cytokine production (TNFα, IFN-β, and IFN-γ), and provides robust protection against DOX-induced cardiac dysfunction and mortality. Our findings delineate the PPP1R3G-RIPK1-ZBP1 axis as the central relay converting a protective phosphorylation checkpoint into a sustained death program. These results identify PPP1R3G as a critical gatekeeper of cardiac viability and a promising therapeutic target for mitigating chemotherapy-induced cardiotoxicity.