AUTHOR=Wu Sixuan , Tang Yuanbin , Pan Junfan , Zheng Yaqin , Pan Qihong , Liang Renji , Xu Haipeng , Li Jiancheng 

TITLE=ZDHHC5 as a central regulator in a palmitoylation-associated prognostic model for lung adenocarcinoma: insights from pan-cancer and experimental analyses

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1643112

DOI=10.3389/fimmu.2025.1643112

ISSN=1664-3224

ABSTRACT=BackgroundProtein S-palmitoylation is a reversible post-translational modification that plays a significant role in tumor progression. However, the impact of palmitoylation metabolism on the prognosis and tumor microenvironment characteristics of lung adenocarcinoma (LUAD) remains unclear.MethodsClinical and mRNA data from LUAD patients were collected from public databases. A palmitoylation-related gene cluster was constructed using consensus clustering. A prognostic model based on palmitoylation-related genes was developed using univariate Cox regression and Lasso regression analysis, and the contribution of each gene was assessed using shapley additive explanations (SHAP) analysis. The role of the key gene ZDHHC5 in LUAD was experimentally validated.ResultsCluster analysis divided patients into two groups, with group B exhibiting a better prognosis. Group A had a higher frequency of TP53 mutations, and significant differences in immune cell infiltration were observed between the two groups. A prognostic risk model, based on five key genes (ZDHHC5, ZDHHC12, ZDHHC21, LYPLA1, and PPT2), revealed significant survival differences between the high-risk and low-risk groups. Immune infiltration analysis showed differences in immune cell lineages and functional activities between risk groups. Drug sensitivity analysis indicated varying patient responses to different chemotherapy drugs across risk strata. Further analysis of ZDHHC5 expression across 33 cancers demonstrated its upregulation in multiple cancers, including LUAD. Experimental results suggest that ZDHHC5 may promote LUAD cell proliferation and metastasis both in vivo and in vitro via the PI3K/AKT pathway.ConclusionA prognostic model based on palmitoylation-related genes offers a valuable tool for survival prediction and the development of personalized treatment strategies in LUAD. ZDHHC5, a key gene related to palmitoylation, demonstrates potential as both a therapeutic target and a prognostic marker for LUAD and other cancers.