结直肠癌（CRC）是一种严重威胁人类健康和生命的恶性肿瘤，其治疗一直是研究中的难点和热点。本研究首次报道了抗精神病药物阿立哌唑（Ari）对CRC细胞在体外和体内增殖的抑制作用，但对正常结肠细胞的损伤较小。结果表明，5-羟色胺2B受体（HTR2B）及其耦合蛋白G蛋白亚单位α q（Gαq）在CRC细胞中高度分布。阿立哌唑与HTR2B亲和力强，并抑制HTR2B下游信号传导。抑制HTR2B信号传导可抑制CRC细胞的生长，但未发现HTR2B具有独立的抗癌活性。有趣的是，阿立哌唑治疗后Gαq与HTR2B的结合减少。Gαq的沉默不仅限制了CRC细胞的生长，还直接影响了阿立哌唑的抗CRC效果。此外，在氨基酸190位点发生突变的Gαq中发现了阿立哌唑与Gαq的相互作用，降低了阿立哌唑的功效。因此，这些结果证实Gαq与HTR2B偶联是阿立哌唑介导的CRC增殖的潜在靶点。综上所述，本研究为CRC的治疗提供了一种新的有效策略，并为推广阿立哌唑作为抗癌药物提供了有利的证据。 ©2023中国药学会和中国医学科学院药物所。Elsevier B.V.制作和托管。

Colorectal cancer (CRC) is a type of malignant tumor that seriously threatens human health and life, and its treatment has always been a difficulty and hotspot in research. Herein, this study for the first time reports that antipsychotic aripiprazole (Ari) against the proliferation of CRC cells both in vitro and in vivo, but with less damage in normal colon cells. Mechanistically, the results showed that 5-hydroxytryptamine 2B receptor (HTR2B) and its coupling protein G protein subunit alpha q (Gαq) were highly distributed in CRC cells. Ari had a strong affinity with HTR2B and inhibited HTR2B downstream signaling. Blockade of HTR2B signaling suppressed the growth of CRC cells, but HTR2B was not found to have independent anticancer activity. Interestingly, the binding of Gαq to HTR2B was decreased after Ari treatment. Knockdown of Gαq not only restricted CRC cell growth, but also directly affected the anti-CRC efficacy of Ari. Moreover, an interaction between Ari and Gαq was found in that the mutation at amino acid 190 of Gαq reduced the efficacy of Ari. Thus, these results confirm that Gαq coupled to HTR2B was a potential target of Ari in mediating CRC proliferation. Collectively, this study provides a novel effective strategy for CRC therapy and favorable evidence for promoting Ari as an anticancer agent.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.