Hepatic MFSD2A expression is associated with MASLD improvement after bariatric surgery

Abstract Background Bariatric surgery effectively ameliorates metabolic dysfunction-associated steatotic liver disease (MASLD); however, its influence on hepatic gene expression remains poorly defined. This study analyzed transcriptomic profiles from the Gene Expression Omnibus (GEO) database to screen differentially expressed genes, and further explored the regulatory role of MFSD2A (major facilitator superfamily domain containing 2 A) in hepatic lipid metabolism. Methods Public transcriptomic datasets (GSE106737, GSE125946) were analyzed to identify overlapping differentially expressed genes (DEGs) across cohorts. Candidate genes associated with MASLD improvement were screened by consistent expression patterns. MFSD2A expression was measured in patients before and after surgery and correlated with weight loss and BMI (body mass index). Functional validation was performed in HFD (high-fat diet)-fed mice and primary hepatocytes using MFSD2A knockdown to clarify its role in fatty acid metabolism. Results The analysis prioritized MFSD2A as a candidate gene, which was consistently upregulated in MASLD conditions and downregulated after bariatric surgery across multiple datasets. Another candidate gene, DUSP1, could not be validated because of primer design or amplification issues, and therefore was not carried forward. The downregulation of hepatic MFSD2A expression after bariatric surgery was positively associated with weight loss and BMI reduction. In HFD-fed mice, MFSD2A expression increased progressively during MASLD development. In mouse primary hepatocytes, MFSD2A knockdown markedly attenuated free fatty acid (FFA)-induced lipid accumulation, which was associated with the downregulation of fatty acid transporters CD36 and FATP1. Conclusions This study demonstrates that MFSD2A expression correlates with MASLD progression and decreases after bariatric surgery. MFSD2A may influence hepatic lipid accumulation in MASLD, although a direct causal relationship cannot be established from these observational data.