Liver-specific SLC13A3 modulation alleviates MASLD by regulating NAD⁺ metabolism

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder with complex pathogenesis and limited therapeutic options. Here, we identify the solute carrier SLC13A3 as a critical regulator of MASLD progression. In a mouse model fed a high-fat, high-cholesterol, and high-fructose (HFHCHF) diet, hepatic SLC13A3 expression was significantly upregulated and positively correlated with disease severity. Liver-specific overexpression of Slc13a3 exacerbated hepatic steatosis, lipid accumulation, and metabolic dysfunction, whereas Slc13a3 knockdown attenuated these pathological phenotypes. Targeted metabolomic analysis revealed that SLC13A3 modulates hepatic NAD⁺ levels, thereby influencing the expression of key lipid metabolism genes, including SREBF1, CD36, PPARγ, and SCD1. These findings highlight a previously unrecognized role of SLC13A3 in MASLD pathogenesis and suggest its potential as a therapeutic target.