Integrative analysis of fatty acid metabolism and identification of ANLN as a novel prognostic marker in lung adenocarcinoma.

Background: Dysregulation of fatty acid (FA) metabolism represents a critical contribution to the tumorigenesis and progression of lung adenocarcinoma (LUAD). This study aimed to identify the roles of FA metabolism and search for potential therapeutic targets. Methods: The genomic and clinical data from The Cancer Genome Atlas (TCGA)-LUAD cohort underwent univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses to establish a FA metabolism-related gene (FAMG) signature. Immunotherapy efficacy was evaluated via the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Pharmacological sensitivity to conventional chemotherapeutic agents and molecular targeted therapies was evaluated using the "pRRophetic" R package. Through integrative multi-omics analysis, ANLN was identified as a key gene with significant prognostic value. Gene silencing via small interfering RNA (siRNA) transfection was employed for functional validation. We further analyzed the biological role and mechanism of ANLN through bioinformatics and experimental analyses in LUAD cell lines. Results: The FAMG prognostic signature indicated clinical utility in predicting patient outcomes and stratifying survival probabilities. The signature showed predictive capacity for therapeutic responses across immunotherapy, chemotherapy, and targeted drugs, supporting precision oncology applications. Experimental validation confirmed that ANLN knockdown significantly attenuated malignant phenotypes through impairing cellular proliferation and migration, enhancing apoptotic induction in LUAD. Mechanistically, we discovered for the first time that ANLN knockdown inhibited FA synthesis, glycolysis, and epithelial-mesenchymal transition (EMT) by downregulating the AKT/mTOR/HIF-1α signaling axis, representing a novel regulatory mechanism in LUAD metabolism. Conclusions: This work delineates FA metabolic heterogeneity and its predictive function of personalized treatment in LUAD. ANLN is established as both a prognostic biomarker and metabolic regulator through modulation of the AKT/mTOR/HIF-1α signaling axis. Our findings provide a framework for developing metabolism-targeted treatment strategies.