S-adenosylmethionine and nicotinic acid suppress Hepatocellular carcinoma proliferation by targeting SLC25A4.

Hepatocellular carcinoma (HCC), an incurable malignancy with limited therapeutic options, exhibits mitochondrial dysfunction upon co-treatment with S-adenosylmethionine (SAM) and nicotinic acid (NA); however, the underlying mechanisms were undefined. Transcriptomic analysis identified dysregulation of the solute carrier (SLC) family gene SLC25A4. Subsequent experiments confirmed that SAM-NA co-treatment upregulates SLC25A4 (ANT1) expression and nicotinamide adenine dinucleotide (NAD+) levels. Molecular docking and surface plasmon resonance (SPR) analyses suggest direct SLC25A4-NAD+ interaction. Elevated NAD+ activates sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), leading to remodeling of lipid metabolism. This remodeling impairs mitochondrial lipid transport and results in neutral lipid accumulation, thereby suppressing HCC proliferation. In situ xenograft models validate the safety of the treatment. This study proposes a stratified therapeutic approach: targeting the SLC25A4-NAD+-SIRT1-AMPK axis may benefit HCC patients with preserved SLC25A4 expression.