Objective <p>To investigate the expression characteristics, prognostic value, and role of COL11A1 in Sorafenib resistance in lung adenocarcinoma (LUAD).</p> Methods <p>The expression differences of COL11A1 in LUAD were analyzed based on The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis was performed to evaluate prognostic value, and drug sensitivity analysis, molecular docking analysis and molecular dynamics simulation were conducted. Molecular mechanisms were explored using Weighted Gene Co-expression Network Analysis (WGCNA) and functional enrichment analysis. A549/Sorafenib-resistant and H1299/Sorafenib-resistant cell line was established, and the effects of COL11A1 knockdown and overexpression on cell proliferation, apoptosis, migration, and invasion were examined. Western blot was performed to assess the protein expression levels of p-Akt, E-cadherin, and Vimentin to explore the underlying molecular mechanisms.</p> Results <p>COL11A1 was significantly upregulated in LUAD, and patients with high expression showed poor prognosis. Drug sensitivity analysis, molecular docking analysis and molecular dynamics simulation revealed that COL11A1 was associated with Sorafenib. Functional analysis indicated that COL11A1 primarily participated in extracellular matrix remodeling and collagen metabolic processes. Cell experiments confirmed that COL11A1 was highly expressed in resistant cells. Mechanistically, COL11A1 was found to activate the Akt signaling pathway and promote epithelial-mesenchymal transition (EMT) in Sorafenib-resistant LUAD cells, as evidenced by elevated p-Akt and Vimentin levels alongside reduced E-cadherin expression.</p> Conclusion <p>COL11A1 mediates Sorafenib resistance by inhibiting tumor cell apoptosis, activating the Akt signaling pathway, and promoting EMT, and can serve as a potential prognostic biomarker and therapeutic target for overcoming drug resistance in LUAD.</p>