YY1-induced USP43 drives ferroptosis suppression by FASN stabilization and subsequent activation of SLC7A11 in ovarian cancer.

Abstract

The ubiquitin-specific protease (USP) family is a major member of the deubiquitinating enzyme family that plays important and diverse roles in multiple tumors. The roles and mechanisms of action of USP family members in ovarian cancer are not well understood. This study aimed to screen all the USP family members and explored the specific function of USP43 in ovarian cancer. The expression levels of USP family members in ovarian cancer were screened using bioinformatics analysis, and the specific function of USP43 was explored through in vitro and in vivo experiments. Functional assays, including cell viability, ferroptosis, and tumor xenograft models, were employed. In short, USP43 drives the ferroptosis suppression by activating the expression of SLC7A11 through FASN-HIF1α pathway. USP43 is an important prognostic factor for ovarian cancer, with its overexpression promoting ovarian cancer progression and its knockdown inhibiting it. Mechanistically, USP43, which is transcriptionally activated by YY1, stabilizes FASN through deubiquitination, and FASN activates SLC7A11 expression by stabilizing HIF1α. Furthermore, the combination of cisplatin and the SLC7A11 inhibitor HG106 significantly inhibits the growth of ovarian tumors. Thus, targeting the USP43-FASN-HIF1α-SLC7A11 axis can inhibit ferroptosis and promote platinum sensitivity in ovarian cancer.