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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

SUBMITTER: 雷名 吴  

LAB HEAD: Leiming Wu

PROVIDER: PXD058272 | Pride | 2025-10-20

REPOSITORIES: Pride