zDHHC-mediated palmitoylation modification patterns and tumor immune microenvironment infiltration characterization in pancreatic cancer.

[BACKGROUND] Protein palmitoylation, catalyzed by the zDHHC family of palmitoyltransferases, has emerged as a critical post-translational modification implicated in tumor progression. However, the comprehensive role of zDHHCs-mediated palmitoylation in molecular subtyping, prognosis, and immune microenvironment modulation in pancreatic cancer (PC) remains unclear.

[METHODS] We systematically integrated multi-cohort transcriptome, single-cell RNA-seq, and somatic mutation data for PC. Bioinformatic analyses included molecular subtyping based on zDHHCs expression, differential gene expression, functional enrichment, CIBERSORTx-based immune infiltration analysis, single-cell trajectory inference, cell-cell communication networks, and construction/validation of a palmitoylation-related gene signature (PRGS) prognostic model.

[RESULTS] Two robust molecular subtypes based on zDHHCs expression were identified, displaying significant differences in patient prognosis and immune infiltration. High zDHHCs activity was associated with immunosuppressive features, including decreased CD8+ T cell infiltration and enrichment of macrophages/eosinophils. Single-cell analyses revealed dynamic upregulation of zDHHCs genes during epithelial differentiation, especially in metastatic lesions, with trajectory and enrichment analyses implicating palmitoylation in proliferation, cell cycle, and chromatin remodeling. Cell-cell communication networks uncovered zDHHCs-dependent remodeling of SPP1-CD44 and MHC-II pathways, linked to immune suppression. A 7-gene PRGS (DCBLD2, CXCL5, ASPH, LAMC2, KRT6A, TOP2A, NPNT) prognostic model demonstrated robust predictive accuracy across independent cohorts, correlating with tumor mutation burden, TP53/KRAS mutation frequency, and activation of proteasome, pyrimidine metabolism, and immune evasion pathways.

[CONCLUSIONS] zDHHCs-mediated palmitoylation and its regulatory gene network critically shape pancreatic cancer heterogeneity, immune microenvironment, and prognosis. The PRGS model provides a novel molecular tool for patient stratification and may inform the development of precision therapies targeting palmitoylation-driven pathways in PC.