Introduction and Objective: Protein lactylation is implicated in MASLD, yet its functional role remains poorly defined. This study investigated the mechanism through which AARS2 regulates SOD2 lactylation to drive MASLD progression.Methods: This study integrated multi-omics data from clinical and preclinical MASLD models to systematically assess AARS2 expression. Lactyl-proteomics identified SOD2 as a key target. Direct AARS2-SOD2 interaction were confirmed by Co-IP, IP-MS, and IF. Site-directed mutagenesis, lactylation-specific antibody and in vitro lactylation assays verified AARS2-specific catalysis of SOD2-K114 lactylation. AARS2-overexpressing/KO mice and SOD2-p.K114R knock-in mice were generated to elucidate the functional role of this modification. Functional consequences were assessed by measuring SOD2 activity, mitochondrial superoxide and respiration.Results: The results showed that AARS2 was upregulated in MASLD patient livers. In vivo, AARS2 overexpression worsened hepatic steatosis, while its knockout attenuated lipid accumulation. Mechanistically, AARS2 directly catalyzed SOD2-K114 lactylation, suppressing its antioxidant function and resulting in mitochondrial superoxide accumulation, metabolic impairment, and accelerated MASLD progression.Conclusion: Our findings unravel the mechanism by which AARS2 regulates SOD2 lactylation and indicate that targeting AARS2-SOD2 Kla may be a promising strategy for MASLD therapy.
Q. He: None. W. He: None. H. Ren: None. G. Yuan: None.
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