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Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System
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Published on: April 11, 2025

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

Xueling Ma, Ken Chen, Zhigao Wang

    Biorxiv : the Preprint Server for Biology
    |October 3, 2025
    PubMed

    Insights

    Doxorubicin (DOX) chemotherapy causes heart damage by activating cell death pathways. Protein Phosphatase 1 Regulatory Subunit 3G (PPP1R3G) amplifies this toxicity, making it a potential target for cardioprotection.

    Area of Science:

    • Molecular Biology
    • Cardiology
    • Oncology

    Background:

    • Cardiotoxicity is a significant challenge in cancer chemotherapy, particularly with drugs like doxorubicin (DOX).
    • The precise molecular mechanisms driving DOX-induced cardiotoxicity are not fully understood.

    Purpose of the Study:

    • To identify key molecular players involved in doxorubicin-induced cardiotoxicity.
    • To elucidate the role of Protein Phosphatase 1 Regulatory Subunit 3G (PPP1R3G) in mediating cardiac cell death.

    Main Methods:

    • Investigated DOX-induced apoptosis and necroptosis in cardiomyocytes in vitro.
    • Utilized genetic ablation of Ppp1r3g in vivo to assess its protective effects.
    • Examined the phosphorylation status of receptor-interacting protein kinase 1 (RIPK1) and downstream signaling pathways.

    Main Results:

    • DOX induces both apoptosis and necroptosis, initially transiently inhibited by p38-dependent RIPK1 phosphorylation.
    • PPP1R3G removes inhibitory phosphorylation on RIPK1, promoting sustained cell death signaling.
    • Activated RIPK1 triggers mitochondrial DNA release, IFN-β production, ZBP1 expression, and amplifies necroptosis.
    • Ppp1r3g knockout mice showed reduced cardiac cell death, inflammation, and protection from DOX-induced injury.

    Conclusions:

    • The PPP1R3G-RIPK1 axis is a critical mediator of DOX cardiotoxicity, converting an early protective brake into sustained death signaling.
    • Targeting PPP1R3G offers a potential therapeutic strategy for preventing chemotherapy-induced heart damage.

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