药物再利用是扩大肿瘤学治疗范围的一种吸引人的策略。托尔吡咯索是一种用于治疗长期疼痛病症的旧型中枢性肌肉松弛剂。本研究调查了托尔吡咯索在人类癌症中的治疗效果和机制，并探讨了与蛋白酶体抑制剂和免疫治疗的联合策略。通过测量半最大抑制浓度、细胞死亡和细胞生长来评估托尔吡咯索的抗肿瘤效果。采用RNA测序、免疫印迹、分子对接、酶活性分析和ChIP-qPCR等方法揭示其潜在机制。以异种移植模型评估托尔吡咯索单独或与蛋白酶体抑制剂或免疫治疗联合应用的疗效。托尔吡咯索抑制人类癌细胞的生长并诱导细胞死亡。托尔吡咯索处理的细胞中超激活了未折叠蛋白应答（UPR）通路。我们进一步确定了组蛋白赖氨酸特异性去甲基化酶1（LSD1）作为托尔吡咯索的潜在靶点，该靶点直接去甲基化H3K4me2上的UPR相关基因。托尔吡咯索通过增强UPR协同改善了MG132的疗效，并通过将M2巨噬细胞转化为M1表型来增强肿瘤对免疫治疗的敏感性。托尔吡咯索通过靶向LSD1抑制人类癌症。结合策略在癌症治疗中再利用托尔吡咯索具有临床潜力。

Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy.The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death and cell growth. RNA sequencing, western blotting, molecule docking, enzyme activity assay and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy.Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype.Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by combination strategy implies clinical potential.