Targeting LINC01607 sensitizes hepatocellular carcinoma to Lenvatinib via suppressing mitophagy.

Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma (HCC), but resistance limits clinical benefits. In this study, we identified inhibition of ROS levels and reduced redox status in Lenvatinib-resistant HCC. Integrating RNA-seq with unbiased whole-genome CRISPR-Cas9 screen analysis indicated LINC01607 regulated the P62 to enhance drug resistance by affecting mitophagy and antioxidant pathways. Underlying mechanisms were investigated both in vitro and in vivo. We initially confirmed that LINC01607, as a competing endogenous RNA (ceRNA) competing with mirRNA-892b, triggered protective mitophagy by upregulating P62, which reduced ROS levels and promoted drug resistance. Furthermore, LINC01607 was proved to resist oxidative stress by regulating the P62-Nrf2 axis, which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop. Finally, silencing LINC01607 combined with Lenvatinib reversed resistance in animal and patient-derived organoid models. In conclusion, we proposed a novel mechanism of Lenvatinib resistance involving ROS homeostasis. This work contributed to understanding redox homeostasis-related drug resistance and provided new therapeutic targets and strategies for HCC patients.