ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1643112
ZDHHC5 as a central regulator in a palmitoylation-associated prognostic model for lung adenocarcinoma: insights from pan-cancer and experimental analyses
Provisionally accepted
- 1Fujian Medical University, Fuzhou, China
- 2The First Affiliated Hospital, University of South China, Hengyang, China
- 3Fuzhou University, Fuzhou, China
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Background: Protein 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. Methods: Clinical 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. Results: Cluster 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. Conclusion: A 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.
Keywords: palmitoylation, Lung Adenocarcinoma, Prognostic model, ZDHHC5, Immune infiltration
Received: 08 Jun 2025; Accepted: 03 Sep 2025.
Copyright: © 2025 Wu, Tang, Pan, Zheng, Pan, Liang, Xu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jiancheng Li, Fujian Medical University, Fuzhou, China
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