USP11 is involved in the sensitivity of liver cancer cells to ferroptosis and taxanes through the regulation of NRF2 ubiquitin-mediated degradation

Background: Ubiquitin-Specific Protease 11 (USP11) plays a significant role in tumor progression through various mechanisms. However, in hepatocellular carcinoma (HCC) research, the mechanism by which USP11 impacts Ferroptosis and sensitivity to taxanes in HCC remains ambiguous. The aim of this study was to investigate the effects of USP11 on Ferroptosis and sensitivity to taxanes in HCC.

Methods: Research was conducted on clinical HCC specimens, cell lines (THLE2, HepG2, SNU449, Huh7, and Hep3B), and subcutaneous tumorigenesis models. Gene and protein expression was detected using real-time quantitative polymerase chain reaction (RT‒qPCR), western blotting, and immunohistochemistry. Cell proliferation and migration were detected using cell counting kit-8 (CCK-8), colony, scratch, and Transwell assays. Ferroptosis was evaluated by Fe²⁺, glutathione (GSH), malondialdehyde (MDA) and Reactive Oxygen Species (ROS)-related indices.

Results: USP11 was upregulated in HCC clinical tissues, and overexpression or knockdown of USP11 promoted or inhibited the proliferation, migration and invasion of HCC cells in vitro, respectively. Furthermore, when triggered by erastin, overexpression of USP11 led to a reduction in Fe²⁺, MDA, and ROS levels in HepG2 and SNU449 cells but an increase in GSH, solute carrier family 7 member 11 (SLC7A11), and Glutathione Peroxidase 4 (GPX4), thus inhibiting Ferroptosis in HCC cells. USP11 also inhibited the sensitivity of HCC cells to taxanes (paclitaxel, docetaxel, and cabazitaxel). From a mechanistic standpoint, USP11 enhanced nuclear factor erythroid-2-related factor 2 (NRF2) expression via deubiquitination, thus reducing Ferroptosis and taxane sensitivity in HCC cells.

Conclusion: This research highlights the crucial role of USP11 in Ferroptosis and drug resistance in HCC, identifying a new potential target for the treatment of HCC.

Ferroptosis; Liver cancer; NRF2; Taxanes; USP11.