ArticleCellular & molecular biology letters2026
Exercise suppresses IP6K3 to modulate BCAA metabolism and ferroptosis in MASLD.
Article in Cellular & molecular biology letters, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Programmed cell death in metabolic syndrome: From molecular mechanisms to therapeutic strategies (Review).International journal of molecular medicine · 2026Review
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14 authors.
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Abstract
backgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is linked to branched-chain amino acid (BCAA) dysmetabolism and ferroptosis, and exercise is considered protective, yet the underlying mechanisms remain unclear.
methodsIntegrated bioinformatic analyses of public datasets were performed to identify key regulators of MASLD. Hepatic inositol hexakisphosphate kinase 3 (IP6K3) expression was examined in liver samples from patients with MASLD as well as mice. The functional role of IP6K3 was assessed by either hepatocyte-specific Ip6k3 deletion or exercise intervention in mice. Single-cell RNA sequencing (scRNA-seq), IP6K3 overexpression and knockdown, liquid chromatography-tandem mass spectrometry, and co-immunoprecipitation were used to explore the underlying mechanism by which IP6K3 regulates MASLD.
resultsHepatic IP6K3 was significantly upregulated in both patients with MASLD as well as mice, and exercise markedly attenuated hepatic IP6K3 expression in MASLD mice. Hepatocyte-specific Ip6k3 deletion conferred resistance to MASLD-induced liver injury. scRNA-seq revealed that these protective effects were related to enhanced BCAA degradation and inhibition of ferroptosis. Further studies showed that BCAA degradation was dependent on branched-chain aminotransferase 2 (BCAT2). In vitro, IP6K3 overexpression exacerbated BCAA-promoted ferroptosis, which was rescued by ferrostatin-1. Conversely, IP6K3 knockdown prevented ferroptosis, and this effect was abolished by inhibiting BCAT2. Mechanistically, elevated IP6K3 in MASLD could bind to heterogeneous nuclear ribonucleoprotein K (HNRNPK) in hepatocytes. Exercise-downregulated IP6K3 facilitated HNRNPK release, thereby stabilizing BCAT2 mRNA, promoting BCAA catabolism, and ultimately preventing ferroptosis in MASLD.
conclusionsOur study identifies IP6K3 as a key molecule in exercise-induced protection against MASLD, and suggests that IP6K3 inhibition might represent a potential pharmacological strategy for MASLD intervention.
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