Exercise suppresses IP6K3 to modulate BCAA metabolism and ferroptosis in MASLD

Metabolic 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.

Integrated 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.

Hepatic 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.

Our 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.