Induction of UBQLN1 ‐mediated PGC1α stability by isoliensinine overcame hypoxia‐induced resistance in liver cancer cells

Hypoxia is a key reason for the failure of liver cancer therapy. Emerging evidences indicated that ROS played a crucial role in the sorafenib therapy, and overcoming the reduction in intracellular ROS levels was the first requirement for therapy resistance. Ubiquilin1 (UBQLN1) acted as an oncogene or suppressor gene involved in the protein degradation and abnormal protein aggregation. In this study, we proposed a novel strategy to reverse the hypoxia-induced resistance in liver cancer by isoliensinine (Iso), a significant bioactive compound derived from lotus seed. Based on preliminary screening, we found a significant elevation of UBQLN1 in liver cancer tissues obtained from the TCGA databases and in liver cancer cells under hypoxic model, which contributed to hypoxia-induced sorafenib resistance. Further data suggested that Iso significantly reversed the hypoxia-induced sorafenib resistance through directly targeting UBQLN1 and inducing ROS production. Notably, the ROS elevation induced by Iso could trigger IRP2-induced ferroptosis but remained below the threshold for mitochondrial damage in liver cancer cells. The related mechanism was that Iso reduced the binding between PGC1α and ubiquitin, promoting the stability of the PGC1α protein, which might accelerate mitochondrial energy metabolism. Taken together, our findings not only revealed that UBQLN1 played a critical role in ROS regulation, but also uncovered a previously unrecognized reversal mechanism of Iso in liver cancer, which promoted sensitization of sorafenib-induced ferroptosis by inhibition of UBQLN1/PGC1α pathway under hypoxia.