胶质瘤是最常见的原发性恶性脑肿瘤，生存率较低。虽然依然对利用蛔蚓酶抑制胶质瘤细胞进展具有抗癌药理作用，但其分子靶点及作用机制尚不明确。本研究观察到，蛔蚓酶在剂量和时间上能够抑制胶质瘤的侵袭、迁移和增殖。从机制上来看，蛔蚓酶通过降低mTOR及其下游底物ULK1、P70S6K和4EBP1的磷酸化水平，活化LC3-II而非Caspase-3，诱导胶质瘤细胞进行自噬性死亡。此外，蛔蚓酶通过抑制胶质瘤细胞来源的异种移植模型（CDX）小鼠中的mTOR活性和LC3-II的激活，进一步抑制了胶质瘤的生长并引起自噬的改变。综上所述，本研究结果揭示了蛔蚓酶通过自噬激活抑制胶质瘤进展的新的抗癌机制，该机制可能通过抑制mTOR信号通路来实现，从而提供了蛔蚓酶作为潜在有效的胶质瘤治疗药物的分子基础。© 2023 The Authors. Journal of Cellular and Molecular Medicine由细胞与分子医学基金会和约翰威利和儿子有限公司发表。

Glioma is the most common primary malignant brain tumour, and survival is poor. Hirudin has anticancer pharmacological effects through suppression of glioma cell progression, but the molecular target and mechanism are poorly understood. In this study, we observed that hirudin dose- and time-dependently inhibited glioma invasion, migration and proliferation. Mechanistically, hirudin activated LC3-II but not Caspase-3 to induce the autophagic death of glioma cells by decreasing the phosphorylation of mTOR and its downstream substrates ULK1, P70S6K and 4EBP1. Furthermore, hirudin inhibited glioma growth and induced changes in autophagy in cell-derived xenograft (CDX) nude mice, with a decrease in mTOR activity and activation of LC3-II. Collectively, our results highlight a new anticancer mechanism of hirudin in which hirudin-induced inhibition of glioma progression through autophagy activation is likely achieved by inhibition of the mTOR signalling pathway, thus providing a molecular basis for hirudin as a potential and effective clinical drug for glioma therapy.© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.