Neddylation of STAT3 is a potential therapeutic target for MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) increases the risk of developing steatohepatitis, liver cirrhosis, and liver cancer. Neddylation, a ubiquitin-like post-translational modification, has been proven to play a crucial role in disease progression. Here, we demonstrate that the dysregulation of neddylation is a critical aggravator of MASLD. Treatment with the neddylation inhibitor MLN4924 effectively reduced lipid accumulation and modulated the JAK-STAT signaling pathway by attenuating upstream inflammatory cytokines. Mechanistically, we identified the signal transducer and activator of transcription 3 (STAT3) as a direct neddylation substrate. Our data indicate that neddylation might be essential for acetylation-induced STAT3 dimerization. However, blocking neddylation with MLN4924 concurrently led to the stabilization of CRL-dependent downstream targets, affecting cell cycle and survival pathways. Given the complex and dynamic role of STAT3 in MASLD progression, we further found that combining MLN4924 with a specific STAT3 inhibitor synergistically blocked fatty acid uptake and modulated lipid homeostasis. Overall, our findings uncover a novel regulatory network involving neddylation dysregulation during MASLD progression and highlight the combination of neddylation and STAT3 inhibition as a promising therapeutic strategy.