Beyond DNA Damage: The Impact of Tobacco Smoke and Its Derivatives on MicroRNAs in Lung Cancer Pathogenesis

Tobacco smoking continues to represent the leading risk factor for multiple malignancies, most notably lung cancer (LC), which exhibits a complex molecular pathogenesis. While classical models prioritize direct DNA damage and mutagenesis, growing evidence points to the role of mechanisms not directly dependent on structural DNA lesions. In particular, dysregulation of oncogenic and tumor-suppressive microRNAs (miRNAs) has emerged as a promising area of research. Although numerous miRNAs potentially involved in LC pathogenesis have been reported to be altered by tobacco exposure, the available evidence is fragmented. This heterogeneity, compounded by the chemical complexity of tobacco smoke, prevents the formation of a comprehensive landscape of its pathogenetic mechanisms. This review aims to systematize existing data on tobacco smoke–induced changes in miRNA expression profiles in LC, with reference to individual tobacco smoke constituents, and to identify key biological processes likely modulated by these changes.