Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, but its pathogenesis is unclear. Here we focus on histidine triad nucleotide-binding protein 2 (HINT2), which is expressed in the mitochondria and is involved in hepatic lipid metabolism and mitochondrial protein acetylation. The expression of HINT2 is downregulated in MASLD. HINT2 inhibits free fatty acid-induced lipid accumulation and impairs mitochondrial function in hepatocytes. Hint2 knockout exacerbates diet-induced hepatic steatosis, inflammation, fibrosis and mitochondrial damage in mice. The overexpression of Hint2 attenuates these alterations. Mechanistically, HINT2 regulates mitochondrial protein acetylation via SIRT3; HINT2 enhances the NAD⁺-dependent activation of sirtuin-3 (SIRT3) by promoting the mitochondrial influx of NAD⁺ through solute carrier family 25 member 51 (SLC25A51), thus ameliorating MASLD. Moreover, the downregulation of HINT2 in MASLD is due to YTH N⁶-methyladenosine RNA binding protein 1 (YTHDF1)-mediated regulation. Our results suggest that HINT2 may be an important therapeutic target for MASLD.