ArticleProceedings of the National Academy of Sciences of the United States of America2026
PPP1R3G-RIPK1-ZBP1 axis activates early-stage apoptosis and late-stage necroptosis to promote doxorubicin-induced cardiotoxicity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- PPP1R3G-RIPK1-ZBP1 axis activates early-stage apoptosis and late-stage necroptosis to promote doxorubicin-induced cardiotoxicity.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- ZBP1 contributes to IFN-β-induced PANoptosis-related skeletal muscle cell injury in dermatomyositis.Frontiers in immunology · 2026Article
- Mitochondrial dysfunction-driven PANoptosis in doxorubicin-induced cardiotoxicity: mechanistic insights and intervention strategies.Frontiers in pharmacology · 2026Review
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Abstract
Cardiotoxicity is a dose-limiting complication of doxorubicin (DOX) chemotherapy, yet the molecular mechanisms governing the transition from acute stress to terminal heart failure remain incompletely defined. Here, we identify Protein Phosphatase 1 Regulatory Subunit 3G (PPP1R3G) as a central regulator of a RIPK1-ZBP1 signaling axis that drives DOX-induced cardiotoxicity. We demonstrate that DOX initiates a biphasic death program. Initially, DOX triggers p38-mediated inhibitory phosphorylation of RIPK1, which functions as a transient molecular "brake" against cell death. However, sustained stress recruits PPP1R3G to dephosphorylate RIPK1, "unleashing" its activity and triggering early-stage apoptosis. Activated RIPK1 subsequently promotes the cytosolic release of mitochondrial DNA (mtDNA), which induces Z-DNA-binding protein 1 (ZBP1) expression via an IFN-β signaling circuit. This establishes a lethal feed-forward loop where ZBP1 senses mtDNA to amplify late-stage necroptosis. Genetic ablation of
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