An endophyte-derived small molecule targets LIC1 to suppress lung tumor growth by inducing autophagy

Small molecules that induce autophagy in specific biological contexts will provide invaluable chemical probes and potential anti-cancer therapeutics. Herein, we identified a potent autophagy inducer 18e through screening of an endophyte-derived small molecule library. 18e demonstrates significant anti-tumor efficacy in non-small-cell lung cancer (NSCLC) tumors and sensitizes tumor to anti-PD1 immunotherapy. Utilizing a photoaffinity labeling approach, we identified dynein Light Intermediate Chain-1 (LIC1), a subunit of dynein, as the direct target of 18e. Mechanistically, the targeting of LIC1 by 18e markedly disrupts the interactions between LIC1 and stress-sensing effector RUVBL1. This disruption leads to ribosome collision, subsequently activating the downstream GCN2-eIF2α-ATF4 axis-mediated integrated stress response (ISR), which ultimately facilitates autophagic cell death. Our findings not only define LIC1 as a novel therapeutic target for NSCLC, but also underscore the potential of 18e as a promising autophagy inducer for treatment of this disease.

在特定生物学情境中诱导自噬的小分子，将成为极具价值的化学探针与潜在抗癌治疗药物。本研究通过筛选内生菌来源的小分子化合物库，发现了一种强效自噬诱导剂18e。18e在非小细胞肺癌（non-small-cell lung cancer, NSCLC）模型中展现出显著的抗肿瘤活性，同时可使肿瘤对抗PD-1免疫治疗增敏。本研究采用光亲和标记法，确认动力蛋白轻中间链-1（dynein Light Intermediate Chain-1, LIC1）——动力蛋白的一个亚基——为18e的直接作用靶点。从机制层面而言，18e靶向LIC1后，可显著破坏LIC1与应激感应效应蛋白RUVBL1之间的相互作用。该相互作用的破坏会引发核糖体碰撞，进而激活下游GCN2-eIF2α-ATF4信号轴介导的整合应激反应（integrated stress response, ISR），最终诱导自噬性细胞死亡。本研究的发现不仅将LIC1确立为非小细胞肺癌的全新治疗靶点，同时也证实了18e作为极具潜力的自噬诱导剂用于该疾病治疗的应用前景。