LINC01607 Through P62-dependent Mitophagy And P62/Nrf2-dependent Antioxidant Pathway Promotes Lenvatinib Resistance In Hepatocellular Carcinoma

Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma(HCC),but resistance ultimately limits its clinical benefits.Accumulating evidence indicates that cancer cells can overcome the overproduction of reactive oxygen species(ROS)and tolerate oxidative stress-induced cell death to acquire resistance.Nevertheless,the detailed mechanism of oxidative homeostasis in Lenvatinib resistance is unclear.In this study,Lenvatinib-resistant cells were established by exposure to increasing Lenvatinib concentrations,and found the antioxidant capacity of drug-resistant cells was enhanced.The RNA sequencing,genome-wide CRISPR/Cas9 library screening and HCC tissues indicated abnormal upregulation of LINC01607 and SQSTM1/P62.LINC01607 could promote HCC cell proliferation,metastasis and Lenvatinib resistance.Further investigation demonstrated the expression of LINC01607 was positively correlated with P62 and predicted poor clinical prognosis.Underlying mechanisms were investigated both in vitro and in vivo.We initially confirmed that LINC01607,as a ce RNA by competing with mi R-892 b,triggered protective mitophagy by up-regulating P62,which reduced ROS level and promoted drug resistance.Furthermore,LINC01607/P62 axis was proved to resist oxidative stress and lead to ferroptosis resistance by regulating Nrf2,which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop.Finally,silencing LINC01607 combined with Lenvatinib reversed Lenvatinib resistance in vivo animal and patient-derived organoid model.In conclusion,we proposed a novel mechanism of Lenvatinib drug resistance involving ROS homeostasis,mitophagy and Nrf2.This work contributed to the understanding of oxidative homeostasis-related drug resistance and provided new therapeutic targets and strategies for HCC patients.