Ubiquitin-specific protease 13 modulates cisplatin resistance and ferroptosis of ovarian cancer by stabilizing LGR4 protein

Abstract Background Ubiquitination, a crucial post-translational modification, plays a vital role in cancer progression. The present research focused on the function of ubiquitin-specific protease 13 (USP13) and its potential mechanism related to leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) in cisplatin (DDP) resistance and ferroptosis of ovarian cancer (OC). Methods Real-time quantitative PCR and Western blotting were used for mRNA and protein detection. The half-maximal inhibitory concentration (IC50) of DDP was determined using CCK-8 assay. Cell proliferation, apoptosis, and migration were assessed through colony formation/EdU assays, flow cytometry, and transwell/wound healing assays, respectively. Ferroptosis was analyzed by detecting reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), Fe 2+ level and protein marker expression. Co-immunoprecipitation (Co-IP) assay was applied for protein interaction and ubiquitination analysis. Xenograft studies were constructed for in vivo research. Results LGR4 expression was increased in DDP-resistant OC tissues and cell lines. After LGR4 was downregulated, chemoresistance and malignant characteristics such as proliferation and migration were suppressed while ferroptosis was promoted in DDP-resistant OC cells. USP13 served as a deubiquitinating enzyme to enhance LGR4 protein stability. USP13 inhibition attenuated DDP resistance and promoted ferroptosis by targeting LGR4. LGR4 knockdown could enhance chemosensitivity of tumor tissues to DDP in mice. Conclusion These findings elucidated that USP13 stabilized LGR4 protein to regulate DDP resistance and ferroptosis in OC. Targeting the USP13/LGR4 axis represents a potential therapeutic strategy to overcome DDP resistance in OC. Highlights LGR4 inhibition reduces chemoresistance and promotes ferroptosis in cisplatin-resistant ovarian cancer cells. USP13 stabilizes LGR4 protein by deubiquitination. LGR4 can reverse the effects of USP13 knockdown on cisplatin resistance and ferroptosis