A small molecule targets LIC1 to suppress lung tumor growth by inducing autophagy.

Small molecules that induce autophagy in specific biological contexts can provide invaluable chemical probes and potential anticancer therapeutics. Here we identified a potent autophagy inducer 3,4-diisobutyryl derivative of auxarthrol A (DAA) from an endophyte-derived small-molecule library. DAA demonstrates notable antitumor efficacy in non-small cell lung cancer (NSCLC) tumor and sensitizes tumors to anti-PD1 immunotherapy. Using a photoaffinity labeling approach, we identified light intermediate chain 1 (LIC1), a subunit of dynein, as the direct target of DAA. We found that LIC1 is overexpressed in NSCLC tumors and correlates with poor survival. Mechanistically, the targeting of LIC1 by DAA markedly disrupts the interactions between LIC1 and stress-sensing effector RuvB-like AAA ATPase 1, which in turn elevates downstream GCN2-eIF2α-ATF4 axis-mediated integrated stress response, ultimately promoting autophagic cell death. Our findings define LIC1 as a novel therapeutic target for NSCLC and highlight the potential of DAA as a promising autophagy inducer for treatment of this disease.