[摘 要] 目的：基于加权基因共表达网络分析（WGCNA）探讨贝沙罗汀治疗双打击淋巴瘤（DHL）的分子机制，为DHL治疗提 供潜在靶点和实验依据。方法：从基因表达综合数据库（GEO）下载GSE44164和GSE43677表达谱数据集，筛选出差异表达基因 （DEG）。采用WGCNA识别与DHL相关的基因模块，构建蛋白质相互作用（PPI）网络以筛选关键基因。通过药物预测平台 EpiMed进行关联分析以确定DHL的潜在靶向治疗药物。利用CCK-8法和WB法检测贝沙罗汀对DHL细胞增殖及关键蛋白表 达的影响，通过流式细胞术评估贝沙罗汀诱导细胞凋亡的效果。结果：WGCNA识别出与DHL高度相关的碧绿色模块，在PPI 网络中筛选出10个枢纽基因，包括COL1A2、COL3A1、MMP2、COL5A2、DCN、BGN、FN1、MMP9、FBN1和LUM。药物关联分析 确定贝沙罗汀为潜在治疗药物。体外实验显示，贝沙罗汀显著抑制U2932细胞活力（P < 0.05）、促进细胞凋亡（P < 0.001）、下调细 胞中c-Myc和COL1A2的表达（均P < 0.05）。结论：贝沙罗汀可能通过抑制c-Myc信号通路及调控细胞外基质相关基因发挥抗 DHL作用，其体内疗效及联合治疗潜力需进一步验证。

[Abstract] Objective: To 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. Methods:The 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. Results:WGCNA 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). Conclusion: Bexarotene 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.

[基金项目] 国家老年疾病临床医学研究中心多中心RCT临床研究项目（No. NCRCG-PLAGH-20230010）；军队后勤保健课题 （No. 23BJZ25）；国家自然科学基金（No. 72474125）