Background: The Wnt/beta-catenin signaling pathway is a key regulator of cellular processes, with its dysregulation implicatedin various cancers, including lung cancer. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, has emerged as a potentialdownstream target of this pathway.Objectives: The present study explores the regulation of SIRT2 expression by Wnt/beta-catenin signaling and respiratory syncytialvirus (RSV) infection, and their roles in lung cancer progression.Methods: Five hundred forty-nine lung cancer cells and MRC5 normal lung cells were used to investigate the interplaybetween RSV infection, Wnt/beta-catenin signaling, and SIRT2. Expression levels of SIRT2 and beta-catenin were assessed by Westernblotting, real-time PCR, and confocal microscopy. The impact of Wnt3a (activator), XAV939 (inhibitor), and SIRT2 modulation oncell proliferation, oncogenic marker expression, and apoptosis were evaluated.Results: Wnt3a treatment increased SIRT2 and beta-catenin expression at transcriptional and protein levels in A549 cells, whileXAV939 reversed this effect. The RSV infection synergistically enhanced SIRT2 expression, with Wnt3a amplifying the effect andXAV939 inhibiting it. Confocal microscopy revealed RSV-induced cytoplasmic accumulation of SIRT2 and beta-catenin. The SIRT2overexpression augmented RSV- and Wnt3a-mediated proliferation and increased cyclin D1 expression, while SIRT2 knockdownsuppressed these effects. Sirtuin 2 and Wnt/beta-catenin signaling synergistically upregulated Ki-67, Snail, and c-Myc, promotingtumor progression. SIRT2 enhanced anti-apoptotic markers (Bcl-2) and inhibited pro-apoptotic markers (cleaved caspase-3 andPARP). The SIRT2 knockdown reversed these effects, inducing apoptosis.Conclusions: The RSV infection activates the Wnt/beta-catenin pathway to upregulate SIRT2, which promotes lung cancerprogression by enhancing cell proliferation, oncogenic marker expression, and anti-apoptotic activity. Targeting SIRT2 and itsregulatory pathways offers a promising therapeutic strategy for combating lung cancer.