Hepatic lipotoxicity, resulting from excessive lipid accumulation in hepatocytes, plays a central role in the pathogenesis of various metabolic liver diseases. Despite recent progress, the precise mechanisms remain incompletely understood. Using excessive exposure to palmitate in hepatocytes as our primary experimental model and mice studies, we aimed to uncover the mechanisms behind hepatic lipotoxicity, thereby developing potential treatments. Our data reveal for the first time that exposure to palmitate leads to downregulated expression of poly (ADP-ribose) polymerase 1 (PARP-1) in hepatocytes, inhibiting its enzymatic activity. Whereas inhibiting PARP-1 worsens palmitate-induced hepatotoxicity, preventing PARP-1 suppression, using nicotinamide adenine dinucleotide (NAD