Cytotechnology

Hepatocellular steatosis, an early stage within the non-alcoholic fatty liver disease (NAFLD) spectrum, is characterized by excessive lipid accumulation and oxidative stress in hepatocytes. This study examined the protective role of Lysine-Proline-Valine (KPV), an endogenous tripeptide derived from α-melanocyte-stimulating hormone, against oleic acid (OA)-induced oxidative damage and lipid accumulation in hepatic epithelial HepG2 cells. OA treatment markedly enhanced hepatic lipid deposition by upregulation of fatty acid synthase (FAS) expression. Treatment with KPV (100 µg/mL) significantly attenuated OA-induced lipid accumulation and suppressed FAS expression without inducing cytotoxicity. Mechanistic analysis revealed that KPV reduced reactive oxygen species generation, thereby preventing activation of extracellular signal-regulated kinase. KPV also downregulated AKT phosphorylation, leading to inhibition of mTORC1 phosphorylation under hepatic steatosis conditions. Furthermore, KPV regulated the phosphorylation of peroxisome proliferator-activated receptor gamma, a key transcription factor in de novo lipogenesis, thereby normalizing FAS expression. These findings suggest that KPV acts as an effective antioxidant regulator of lipogenic signaling and may hold potential as a therapeutic candidate for attenuating hepatocellular steatosis. The online version contains supplementary material available at 10.1007/s10616-026-00967-z.