Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of Metabolic dysfunction-associated steatotic liver disease (MASLD). Ubiquitination modification plays a vital role in regulating the inflammatory response and fibrosis in MASLD process. Here, we performed multi-omics analysis to demonstated that TRIM46 binds directedly with SGPL1, promoting SGPL1 degradation via K48-linked polyubiquitination which subsequently suppresses the activation of downstream lipophagy signaling cascades in MASLD progression.