SIRT2 is associated with prognosis, ferroptosis susceptibility, and immune infiltration in lung adenocarcinoma.

Objective: Lung adenocarcinoma (LUAD) is a highly aggressive malignancy originating from the bronchial epithelium or glandular tissues and represents the most rapidly increasing subtype of lung cancer worldwide. Its high incidence and mortality rates contribute to an overall unfavorable prognosis. Therapeutic options for patients with advanced-stage LUAD remain limited, emphasizing the urgent importance of identifying reliable prognostic biomarkers and novel therapeutic targets. Silent information regulator 2 (SIRT2), a member of the mammalian sirtuin family, has been implicated in multiple cancer types; however, its functional relevance in LUAD has not yet been comprehensively defined. Methods: Data from TCGA and GEO were employed to evaluate SIRT2 expression patterns in LUAD. Functional enrichment approaches were applied to infer the biological pathways potentially regulated by SIRT2. Molecular docking and Gene Set Cancer Analysis (GSCA) were used to examine how SIRT2 expression and drug sensitivity are related, and to identify potential small-molecule interactors. Key candidate targets and compounds were subsequently subjected to in silico docking validation. The bioinformatic predictions were further verified through in vitro functional assays and Western blotting using A549 LUAD cells. Results: SIRT2 expression was markedly downregulated in LUAD tissues, and low SIRT2 levels were closely associated with adverse clinical prognostic features, including pathological stage, gender and primary treatment response. Reduced SIRT2 expression correlated with poorer overall, progression-free, and disease-specific survival. Functional enrichment indicated that SIRT2 is involved in multiple core signaling pathways implicated in LUAD progression. Furthermore, SIRT2 expression was strongly associated with ferroptosis-related pathways and estimated immune cell infiltration. Experimental validation in A549 LUAD cells revealed that SIRT2 is linked to suppressed malignant cellular phenotypes and reduced expression of the ferroptosis suppressor GPX4. Conclusions: Collectively, these findings support SIRT2 as a potential prognostic biomarker for LUAD. The molecular networks and pathways uncovered here advance our understanding of SIRT2 biology and lay a foundation for further research. Additional studies focusing on immune-related signatures correlated with SIRT2 may facilitate the development of novel immunotherapeutic approaches for LUAD.