METTL16 promotes MASLD progression through the regulation of lipid synthesis and immune response.

BACKGROUND: Methyltransferase-like 16 (METTL16) is a recently identified m6A RNA methyltransferase. Although its role in hepatocellular carcinoma has been explored, its function in metabolic dysfunction-associated steatotic liver disease (MASLD) remains elusive. METHODS: Expression profiles of methylation-related genes were analyzed in a cohort comprising 206 MASLD patients and 10 healthy controls. Functional assays were conducted using MASLD cell models and diet-induced mouse models. Bioinformatic analyses were performed to evaluate immune cell infiltration and signaling pathway activation. Potential transcriptional regulators and small-molecule inhibitors of METTL16 were predicted through multiple databases. RESULTS: METTL16 expression was markedly upregulated in MASLD tissues and closely correlated with lipid metabolism-related pathways. Knockdown of METTL16 alleviated hepatic steatosis, insulin resistance, and fibrosis in high-fat diet-fed mice. Mechanistically, cell death-inducing DFF45-like effector family members A (CIDEA) was identified as a downstream mediator of METTL16-driven hepatic steatosis. Elevated hepatic METTL16 expression was associated with increased infiltration of innate immune cells, activation of immune-related signaling pathways, and upregulated expression of pro-fibrotic genes. Database mining further revealed that METTL16 may regulate immune-associated genes at both transcriptional and post-transcriptional levels. Additionally, EGR1 and MYC were identified as potential upstream transcriptional regulators of METTL16, and eleven small molecules were predicted to bind to and inhibit its biological activity. CONCLUSION: METTL16 promotes hepatic steatosis and immune-mediated fibrogenesis in MASLD. Targeting the METTL16-CIDEA axis or inhibiting METTL16 activity may serve as a promising therapeutic strategy for the treatment of MASLD.