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Comprehensive analysis of palmitoylation-related genes reveals prognostic signatures and immune landscape in Lung Adenocarcinoma

bioinformatics
molecular-biology
oncology

Abstract

Abstract
Background:
Lung adenocarcinoma (LUAD) is the most prevalent subtype of non-small cell lung cancer and is characterized by high molecular heterogeneity and poor prognosis. Protein palmitoylation, particularly S-palmitoylation, is a reversible post-translational modification regulating protein localization, signaling, and immune responses. Dysregulated palmitoylation has been implicated in tumor progression and immune evasion, yet its comprehensive role in LUAD remains unclear.
Methods:
We systematically analyzed palmitoylation-related genes (PRGs) in LUAD by integrating data from the GeneCards database and TCGA-LUAD cohort. Differential expression, univariate Cox regression, consensus clustering, LASSO-Cox modeling, immune infiltration, mutation profiling, and drug sensitivity analyses were performed. Findings were validated in GEO datasets, and single-cell RNA sequencing combined with qPCR of clinical samples was used to assess cell type-specific expression and regulatory associations.
Results:
Among 2,166 candidate PRGs, 201 were differentially expressed in LUAD, and 15 were significantly associated with overall survival, including the protective gene ACSM5 and the risk gene SKA3. Consensus clustering defined two molecular subtypes (C1 and C2) with distinct survival outcomes, metabolic and proliferative pathway enrichment, and tumor immune microenvironment profiles. A two-gene prognostic model (ACSM5 and SKA3) robustly stratified patients into high- and low-risk groups, with 3-year AUCs ranging from 0.650 to 0.778 across multiple cohorts. High-risk patients exhibited increased tumor proliferation pathways, higher tumor mutation burden, and reduced immune infiltration, whereas low-risk patients showed active immune signaling and higher stromal and immune scores. Single-cell and qPCR analyses confirmed predominant expression of ACSM5 in macrophages and SKA3 in CD8⁺ T cells and macrophages, with opposing correlations with palmitoylation regulators.
Conclusion:
This study provides a comprehensive characterization of PRGs in LUAD, revealing ACSM5 and SKA3 as key prognostic markers and modulators of the tumor immune microenvironment. Our findings highlight the potential of palmitoylation-based molecular signatures for prognostic assessment and personalized therapeutic strategies in LUAD.
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