ZDHHC12 Palmitoylates HDAC8 to Promote the Progression of Hepatocellular Carcinoma Associated with a Diet High in Saturated Fatty Acids

Abstract Excessive intake of saturated fatty acids (SFAs)—commonly associated with diets rich in fried foods and red meat—significantly increases the risk of hepatocellular carcinoma (HCC). Palmitic acid (PA), the most prevalent type of SFA, is selected as the representative model for this study. Palmitoyltransferases play crucial roles in protein palmitoylation mediated by PA; however, the most significantly altered palmitoyltransferase under high‐SFA dietary conditions remains unidentified. This study reveals zinc finger DHHC‐type palmitoyltransferase 12 (ZDHHC12) as a key protein in PA‐driven HCC progression that functions by stabilizing the oncogenic histone deacetylase 8 (HDAC8). Mechanistically, PA supplementation upregulates ZDHHC12 expression by activating the transcription factor SWI/SNF‐related BAF chromatin remodeling complex subunit ATPase 4 (SMARCA4). ZDHHC12 mediates HDAC8 palmitoylation at cysteine 244, thereby inhibiting its lysosomal degradation and ultimately promoting HCC progression. This study reveals that ZDHHC12 is a critical mediator of PA‐induced HCC progression and that targeting HDAC8 can suppress this process. These findings offer a potential therapeutic strategy for HCC patients with high dietary intake of SFAs, particularly PA.