ObjectiveTo investigate the molecular mechanisms of bexarotene in treating double hit lymphoma (DHL) based on Weighted Gene Co-expression Network Analysis (WGCNA), thereby providing potential targets and experimental evidence for DHL treatment.MethodsThe gene expression datasets GSE44164 and GSE43677 were downloaded from the Gene Expression Omnibus(GEO) database, and differentially expressed genes (DEGs) were identified. WGCNA was employed to identify gene modules associated with DHL. A protein-protein interaction (PPI) network was constructed to screen for key hub genes. Drug-gene association analysis was conducted using the EpiMed platform to identify potential targeted drugs for DHL. The effects of bexarotene on DHL cell proliferation and key protein expression were evaluated using the CCK-8 assay and Western blotting (WB), and its effects on cell apoptosis was evaluated using flow cytometry.ResultsWGCNA identified a turquoise module highly associated with DHL, and 10 hub genes (COL1A2, COL3A1, MMP2, COL5A2, DCN, BGN, FN1, MMP9, FBN1, and LUM) were screened from the PPI network. Drug association analysis nominated bexarotene as a potential therapeutic agent. In vitro validation demonstrated that bexarotene significantly inhibited U2932 cell viability (P < 0.05), promoted cell apoptosis (P < 0.001), and downregulated c-Myc and COL1A2 expression (P < 0.05).ConclusionBexarotene may exert anti-DHL effects by suppressing the c-Myc signaling pathway and modulating extracellular matrix-related genes. Further studies are warranted to validate its in vivo efficacy and potential for combination therapy.