Abstract
Lung adenocarcinoma (LUAD) remains a leading cause of cancer‑associated mortality with limited prognostic biomarkers. Fatty acid metabolism (FAM) reprogramming serves a pivotal role in tumor progression; however, the functional importance of specific FAM genes, such as ACSBG1, in LUAD remains elusive. In the present study, transcriptomics data from The Cancer Genome Atlas (n=517) and Gene Expression Omnibus‑GSE13213 (n=117) were analyzed to identify FAM‑related differentially expressed genes (DEGs). Least Absolute Shrinkage and Selection Operator regression and Shapley Additive Explanations (SHAP) interpretable analyses established a prognostic model, and in vitro experiments using A549 and H1299 cell lines with ACSBG1 overexpression (OE) and knockdown. Functional assays included Cell Counting Kit‑8, EdU, Transwell and apoptosis analyses. A total of 35 FAM‑related DEGs were identified, which were enriched in PPAR signaling and fatty acid degradation pathways (false discovery rate <0.05). Subsequently, a seven‑gene prognostic model was established, and demonstrated strong predictive power for 1‑, 3‑ and 5‑year survival (area under the curve values: 0.767, 0.769 and 0.700, respectively). SHAP analysis prioritized ACSBG1 as the dominant protective factor, and its low expression was associated with advanced Tumor‑Node‑Metastasis stages and poor survival. Mechanistically, ACSBG1 OE suppressed proliferation, migration and invasion, and promoted apoptosis. Immune profiling revealed ACSBG1 expression was positively correlated with the infiltration of CD4+ T cells, CD8+ T cells and B cells, suggesting its immunomodulatory potential. In conclusion, to the best of our knowledge, the present study established the first FAM‑based prognostic model for LUAD, and identified ACSBG1 as a novel tumor suppressor through dual mechanisms of metabolic regulation and immune microenvironment modulation. The risk score system established in the current study provides a clinically actionable tool for precision oncology, and ACSBG1‑targeted therapy represents a promising strategy against LUAD progression.