Integrated multi-omics and experimental validation reveal DYNLT3 as a tumor suppressor regulated by quercetin in lung...

Lung squamous cell carcinoma (LUSC), a major subtype of non-small cell lung cancer (NSCLC), is associated with poor prognosis due to late-stage diagnosis and limited treatment options. Dynein light chain Tctex-type 3 (DYNLT3) participates in cellular processes such as mitosis and intracellular transport and has been suggested as a potential tumor suppressor in various cancers. However, its role in LUSC remains unclear. This study investigates the expression of DYNLT3 in LUSC and explores its potential as a tumor suppressor. Additionally, we utilized molecular docking, molecular dynamics simulations, and CETSA to assess quercetin (QUE) as a DYNLT3-modulating small molecule, aiming to identify novel therapeutic strategies for LUSC. Our analysis using public databases and experimental validation revealed significantly reduced DYNLT3 expression in LUSC tissues, cell lines, peripheral blood, and patient plasma, with lower expression correlating with poor prognosis. Functional assays, including CCK-8, colony formation, flow cytometry, Transwell migration, wound healing, and Western blotting, demonstrated that DYNLT3 knockdown promoted cell proliferation, migration, and epithelial-mesenchymal transition (EMT). Additionally, it inhibited apoptosis. Conversely, DYNLT3 overexpression suppressed these malignant phenotypes and inhibited tumor growth in nude mice. Treatment with QUE upregulated DYNLT3 in a dose-dependent manner, reversing the malignant phenotype, while DYNLT3 knockdown partially abrogated QUE's anticancer effects. Moreover, bioinformatic analyses suggested that low DYNLT3 expression may be associated with immune checkpoint activation, increased chemokine and receptor levels, and drug resistance, though experimental validation is still required. In conclusion, DYNLT3 acts as a tumor suppressor in LUSC, and the antitumor effects of QUE are partially dependent on the upregulation of DYNLT3. These findings support the potential of DYNLT3 as a diagnostic/prognostic biomarker and therapeutic target for LUSC.