Background <p>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).</p> Methods <p>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), Fe²⁺ 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.</p> Results <p>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.</p> Conclusion <p>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.</p> Highlights <p><OrderedList> <ListItem> <ItemNumber>1.</ItemNumber> <ItemContent> <p>LGR4 inhibition reduces chemoresistance and promotes ferroptosis in cisplatin-resistant ovarian cancer cells.</p> </ItemContent> </ListItem> <ListItem> <ItemNumber>2.</ItemNumber> <ItemContent> <p>USP13 stabilizes LGR4 protein by deubiquitination.</p> </ItemContent> </ListItem> <ListItem> <ItemNumber>3.</ItemNumber> <ItemContent> <p>LGR4 can reverse the effects of USP13 knockdown on cisplatin resistance and ferroptosis</p> </ItemContent> </ListItem> </OrderedList></p>