TRIM33 enhances the ubiquitination of TFRC to enhance the susceptibility of liver cancer cells to ferroptosis

Background: Hepatocellular carcinoma (HCC) is a common malignancy, and ferroptosis is a novel form of cell death driven by excessive lipid peroxidation. In recent years, ferroptosis has been widely utilized in cancer treatment, and the ubiquitination modification system has been recognized to play a crucial role in tumorigenesis and metastasis. Increasing evidence suggests that ubiquitin regulates ferroptosis-related substrates involved in this process. However, the precise mechanism of utilizing ubiquitination modification to regulate ferroptosis for HCC treatment remains unclear.

Methods: In this study, we detected the expression of TRIM33 in HCC using immunohistochemistry and western blotting techniques. The functional role of TRIM33 was verified through both in vitro and in vivo experiments. To evaluate the level of ferroptosis, mitochondrial superoxide levels, MDA levels, Fe2⁺ levels, and cell viability were assessed. Downstream substrates of TRIM33 were screened and confirmed via immunoprecipitation, immunofluorescence staining, and ubiquitination modification experiments.

Results: Our findings demonstrate that TRIM33 inhibits the growth and metastasis of HCC cells both in vitro and in vivo while promoting their susceptibility to ferroptosis. Mechanistically speaking, TRIM33 induces cellular ferroptosis through E3 ligase-dependent degradation of TFRC-a known inhibitor of this process-thus elucidating the specific type and site at which TFRC undergoes modification by TRIM33.

Conclusion: In summary, our study reveals an important role for TRIM33 in HCC treatment while providing mechanistic support for its function. Additionally highlighted is the significance of ubiquitination modification leading to TFRC degradation-an insight that may prove valuable for future targeted therapies.