The CRABP2-MDK Signaling Axis Promotes Lung Adenocarcinoma (LUAD) Progression and Highlights Prognostic Biomarkers.

Lung cancer is the leading cause of cancer-related mortality worldwide, with LUAD being characterized by high incidence and mortality rates. Despite the use of various treatments, including surgery, chemotherapy, immunotherapy, and molecular targeted therapy, the prognosis in LUAD patients remains unfavorable. As a result, the diagnosis and management of LUAD still present major challenges. There is an urgent need to identify novel therapeutic targets. In this study, we analyzed to explore single-cell transcriptomic data (GSE253013 dataset) to investigate epithelial cells heterogeneity in LUAD. Tumor-specific epithelial subpopulations were identified, and the signature genes were evaluated for prognostic, diagnostic potential across several GEO datasets. Functional assays were conducted to validate the role of CRABP2 in lung cancer cells. Xenograft mouse models, rescue experiments and mechanistic analyzes involving ATRA-RAR signaling were further performed to elucidate the molecular mechanism. CRABP2 expression was positively correlated with MDK in LUAD. Functional assays demonstrated that CRABP2 promoted cell proliferation, migration, invasion, and vasculogenic mimicry through activation of the MDK/VEGF/MMP2/9/AKT signaling axis. In vivo xenograft experiments further confirmed that CRABP2 knockdown suppressed tumor growth and angiogenesis. Rescue experiments identified MDK as a critical downstream effector of CRABP2. Mechanistically, CRABP2 enhanced MDK transcription via activation of the ATRA-RAR signaling pathway and increased RARA occupancy at the MDK promoter. Clinically, elevated CRABP2 expression was associated with poor prognosis and showed strong diagnostic performance in LUAD. Collectively, our findings identify CRABP2-ATRA-RAR-MDK signaling axis that drives LUAD progression and angiogenesis. CRABP2 promotes MDK transcription through activation of RAR signaling, thereby enhancing malignant phenotypes and vasculogenic mimicry. These results establish CRABP2 as a promising diagnostic and prognostic biomarker and suggest that targeting the CRABP2-MDK axis may represent a potential therapeutic strategy for LUAD.