Palmitoylation remodeling dictates HCC heterogeneity: implications for subtype-specific prognostication and targeting the YAP-RhoA axis.

Palmitoylation, a critical post-translational modification mechanism, plays a pivotal role in hepatocellular carcinoma (HCC) tumorigenesis and progression. While multiple palmitoylated proteins have been reported to regulate HCC development, systematic characterization of palmitoylation-associated gene signatures and molecular subtyping based on these regulators remains unexplored. Integrated analysis of transcriptomic profiles enabled stratification of HCC into two distinct palmitoylation-associated molecular subtypes through unsupervised consensus clustering. These subtypes exhibited significant heterogeneity in clinical outcomes, tumor microenvironment features, and therapeutic vulnerabilities. A palmitoylation-related prognostic signature was constructed via LASSO-Cox regression. PAL1 showed a marked association with activated cell cycle programs, epithelial-mesenchymal transition (EMT), and WNT/β-catenin signaling. This subtype also correlated with elevated tumor mutation burden (TMB) and poorer patient prognosis. Conversely, PAL2 was closely associated with the expression of differentiation markers and upregulated lipid metabolic processes. Significantly, pronounced molecular divergence characterized the two PAL subtypes. Additionally, ARHGEF3 was critically identified as a key discriminator between the PAL subtypes, and its expression level was significantly correlated with patient prognosis in HCC. ARHGEF3 was upregulated in HCC and demonstrated functional potential to drive tumor cell proliferation and migration, potentially mediated by the YAP-RhoA signaling cascade. Collectively, this study identifies novel molecular biomarkers and thereby establishes a robust framework for clinical translation.