目的 探究非诺贝特抗肾透明细胞癌（ccRCC）的作用及潜在机制。方法 通过在线数据库Swiss Target Prediction、Pharm Mapper、Target Net、Gene Cards、OMIM、TTD等分析非诺贝特、ccRCC和凋亡相关靶点，STRING数据库构建蛋白质-蛋白质相互作用（PPI）网络并通过Cytoscape进行可视化，采用Metascapep平台进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析，通过Auto Dock Tools和PyMOL软件进行分子对接。采用CCK-8法检测非诺贝特对人肾透明细胞癌786-O细胞株、人肾皮质近曲小管上皮细胞株（HK-2）活力的影响；划痕实验、克隆形成实验和流式细胞术分别检测非诺贝特（50、75、100 μmol· L^-1）对786-O细胞迁移、增殖、细胞周期的影响；Hoechst33258染色和流式细胞术检测非诺贝特对786-O细胞凋亡的影响；Western bloting检测非诺贝特对786-O细胞信号转导与转录激活因子3（STAT3）、p-STAT3、B细胞淋巴瘤2蛋白（Bcl-2）、Bcl-2关联X蛋白（Bax）、半胱氨酸天冬氨酸蛋白酶-3（Caspase-3）蛋白表达的影响。结果 网络药理学分析获得非诺贝特、ccRCC和凋亡共同靶点108个，按照网络拓扑分析结果中的度（degree）值筛选出主要核心靶点为STAT3、EGFR、MMP-9、PPARG、RELA、BCL2L；KEGG富集分析表明JAK2-STAT3信号通路在抗ccRCC中发挥重要作用；分子对接结果显示非诺贝特与主要核心靶点STAT3、EGFR、MMP9、PPARG、RELA、BCL2L具有良好的结合活性。体外实验结果表明，与对照组比较，非诺贝特呈浓度和时间相关性抑制786-O和HK-2细胞的生长（P＜0.01、0.001），且对786-O细胞活力的抑制作用强于HK-2细胞；可将786-O细胞周期阻滞在G₁期（P＜0.001）；显著抑制786-O细胞集落形成、迁移能力（P＜0.01、0.001）；显著诱导786-O细胞凋亡（P＜0.001）；显著下调p-STAT和Bcl-2、上调Bax和Caspase-3蛋白表达（P＜0.05）。结论 非诺贝特可能通过下调STAT3抑制ccRCC细胞增殖迁移，诱导凋亡，进而发挥抗ccRCC的作用。

Objective To explore the role and potential mechanism of fenofibrate in the treatment of renal clear cell carcinoma (ccRCC). Methods The online databases such as Swiss Target Prediction, Pharm Mapper, Target Net, Gene Cards, OMIM, TTD were used to analyze the targets of fenofibrate, ccRCC and apoptosis. The STRING database was applied to construct a proteinprotein interaction (PPI) network and visualized using Cytoscape. Molecular function (GO) and pathway (KEGG) enrichment analysis was performed using the Metascapep platform, and Auto Dock Tools and PyMOL software were used for molecular docking. The CCK-8 method was used to detect the effect of fenofibrate on the viability of human renal clear cell carcinoma 786-O cell line and human renal cortical proximal tubular epithelial cell line (HK-2). Scratch assay, clone formation assay, and flow cytometry were used to detect the effects of fenofibrate (50, 75, and 100 μmol·L^-1) on the migration, proliferation, and cell cycle of 786-O cells, respectively. Hoechst33258 staining and flow cytometry were used to detect the effect of fenofibrate on the apoptosis level of 786-O cells. Western blotting was used to detect the effects of fenofibrate on the expression of signal transduction and transcription activator 3 (STAT3), p-STAT3, B-cell lymphoma 2 protein (Bcl-2), Bcl-2 associated X protein (Bax), and Caspase-3 protein in 786-O cells. Results Network pharmacology analysis identified 108 common targets of fenofibrate, ccRCC and apoptosis. Based on the degree values in network topology analysis, the main core targets were selected as STAT3, EGFR, MMP-9, PPARG, RELA and BCL2L. KEGG enrichment analysis revealed that the JAK2-STAT3 signaling pathway played an important role in anticcRCC. The molecular docking results showed that fenofibrate had good binding activity with the main core targets STAT3, EGFR, MMP9, PPARG, RELA and BCL2L. The in vitro experimental results showed that compared with the control group, fenofibrate inhibited the growth of 786-O and HK-2 cells in a concentration - and time-dependent manner (P <0.01, 0.001), and had a stronger inhibitory effect on the viability of 786-O cells than HK-2 cells, 786-O cell cycle could be arrested in G₁ phase (P <0.001), significantly inhibited the colony formation and migration ability of 786-O cells (P <0.01, 0.001), significantly induced apoptosis in 786-O cells (P <0.001), significantly downregulated p-STAT and Bcl-2, upregulated Bax and Caspase-3 protein expression (P <0.05). Conclusion Fenofibrate inhibited the proliferation and migration of ccRCC cells, induced apoptosis, and exerted anti-ccRCC effect by downregulation of STAT3.

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国家自然科学基金资助项目（82274159）;湖南省自然科学基金科药联合基金项目（2022JJ80088）;湖南省卫生健康委员会重点指导课题（202213055529）;湖南省自然科学基金青年项目（2023JJ40485）;湖南省教育厅优秀青年项目（23B0387、22B0355）;中药粉体与创新药物省部共建国家重点实验室培育基地开放基金项目（23PTKF1016）;药学一流学科开放基金项目（研究生创新性实验计划重点支持项目，2021YX07）;湖南省药学一流学科资助项目