Single-Cell Sequencing Has Revealed the Palmitoylation Landscape in Lung Adenocarcinoma and Identified ABHD17C as a Novel Biomarker.

Protein S-palmitoylation, a reversible posttranslational modification, is crucial for tumor progression. However, the palmitoylation landscape in tumor cells and its variability within different tumor cell populations remain underexplored. We analyzed protein palmitoylation using 23 palmitoyl-acyltransferases and 7 de-palmitoyl-acyltransferases. Through copy number variation, pseudotime, enrichment, and cell-cell communication analyses, we explored heterogeneity among epithelial cells in lung adenocarcinoma. Palmitoylation levels are elevated in normal epithelial cells, whereas depalmitoylation predominates in tumor-derived cells. As clinical stage advances, palmitoylation declines and depalmitoylation increases. We identified a C4 epithelial subtype associated with epithelial-to-mesenchymal transition and angiogenesis, marked by low palmitoylation and high depalmitoylation. This subtype, located at the end of the tumorigenic trajectory, shows intense communication with fibroblasts and endothelial cells but minimal interaction with immune cells, indicating enhanced invasiveness and immune evasion. ABHD17C, a key marker of the C4 subtype, was found to regulate tumor cell proliferation, and its knockdown reduced growth and increased apoptosis. We identified a C4 epithelial subtype linked to lung adenocarcinoma metastasis and highlighted ABHD17C as a potential biomarker and therapeutic target.