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

• 成果类型: Article
• 署名作者: Ma, Xueling; Chen, Ken; Wang, Zhigao
• 署名单位: State University System of Florida; University of South Florida
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2603301123
• 发表日期: 2026-04-21
• 页码: e2603301123
• 关键词: doxorubicin; ripk1; ZBP1; necroptosis; BUTYLATED HYDROXYANISOLE; mitochondrial-dna; necrosis; inflammation; phosphorylation; cardiomyopathy; identification; mechanisms; kinase; heart

摘要

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-f3 signaling circuit. This establishes a lethal feed-forward loop where ZBP1 senses mtDNA to amplify late-stage necroptosis. Genetic ablation of Ppp1rag in mice significantly suppresses both apoptosis and necroptosis, attenuates systemic inflammatory cytokine production (TNF alpha, IFN-f3, and IFN-gamma), 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.