Single-Cell Sequencing Reveals the Palmitoylation Landscape in Lung Adenocarcinoma and Identifies ABHD17C as a Novel...

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. This study was designed to analyze protein palmitoylation using 23 palmitoyl-acyltransferases and 7 de-palmitoyl-acyltransferases. Copy number variation, pseudotime, enrichment, and cell-cell communication analyses were used to explore heterogeneity among epithelial cells in lung adenocarcinoma. Palmitoylation levels were elevated in normal epithelial cells, whereas depalmitoylation predominated in tumor-derived cells. As clinical stage advanced, palmitoylation declined and depalmitoylation increased. A C4 epithelial subtype associated with epithelial-to-mesenchymal transition and angiogenesis, marked by low palmitoylation and high depalmitoylation, was identified. This subtype, located at the end of the tumorigenic trajectory, showed 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, regulated tumor cell proliferation, and its knockdown reduced growth and increased apoptosis. A C4 epithelial subtype linked to lung adenocarcinoma metastasis was identified and ABHD17C emerged as a potential biomarker and therapeutic target.