USP14 targets FABP5-mediated ferroptosis to promote proliferation and cisplatin resistance of HNSCC.

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) ranks among the most lethal solid tumors in humans, with a five-year survival rate hovering around 50%. The limited understanding of its biological foundation has hindered the development of efficacious targeted therapeutics.

Methods: TCGA database and immunohistochemistry were deployed to confirm the expression levels of ubiquitin specific protease 14 (USP14). CCK8 method was used to evaluate the influence of USP14 on cisplatin resistance. Further investigations into the role of USP14 were conducted through assessments of cell proliferation, colony formation, and Transwell assays. The impact of USP14 expression on ferroptosis was evaluated by measuring GSH/GSSG ratios, Fe²⁺ concentrations, and lipid peroxide levels. Co-IP was employed to verify the interaction between USP14 and FABP5.

Results: Our analysis revealed that USP14 ranked among the most prominently upregulated deubiquitinases (DUBs) in tissue samples of HNSCC. Notably, aberrant USP14 expression was linked to tumorigenesis and the malignant evolution of HNSCC and further suggested a poor prognosis. In vitro experiment revealed that USP14 depletion markedly inhibited cell growth, cisplatin resistance, invasion and migration capabilities of HNSCC cells. Mechanically, USP14 inhibits FABP5 ubiquitination and degradation, thus positively modulating FABP5 expression. Subsequent analyses demonstrated that the loss of USP14 promoted ferroptosis in HNSCC cells. Finally, in vivo xenograft experiments confirmed that the USP14 small molecular antagonist IU1 could effectively attenuate cisplatin resistance in HNSCC.

Conclusion: The results indicate that the USP14-FABP5 axis exerts oncogenic effects on HNSCC, providing a potential target for diagnosing and treating this type of malignancy.