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MARK4 Drives Mitochondrial Dysfunction–Mediated Cardiomyocyte Pyroptosis via the PKM2–STAT3 in Myocardial Infarction-1

ABSTRACT: Myocardial infarction (MI) remains a major cause of morbidity and mortality, and here we show that microtubule affinity‑regulating kinase 4 (MARK4) is markedly upregulated in human MI samples, mouse myocardium and in vitro cardiomyocyte injury models; using cardiomyocyte‑specific knockout and overexpression models, proteomic analysis and co‑immunoprecipitation (Co‑IP) coupled with LC‑MS/MS were pivotal in delineating the mechanism by which MARK4 exacerbates MI. Proteomics/Co‑IP identified a direct MARK4–PKM2 interaction: MARK4 enhances PKM2 nuclear translocation and phosphorylation, activating STAT3, which transcriptionally suppresses PGC‑1α/β, leading to mitochondrial dysfunction, oxidative stress, NLRP3 inflammasome activation and cardiomyocyte pyroptosis. Genetic deletion or pharmacological inhibition of MARK4 ameliorated MI‑induced cardiac injury, while restoring PKM2 activity or inhibiting STAT3 rescued mitochondrial function and reduced NLRP3 activation, highlighting MARK4 as a potential therapeutic target in acute MI.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Xing Ye

PROVIDER: PXD071966 | iProX | Fri Dec 12 00:00:00 GMT 2025

REPOSITORIES: iProX

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