USP18 promotes cell proliferation and inhibits ferroptosis by stabilizing HDAC3 in endometrial carcinoma

Endometrial cancer (EC) represents one of the most prevalent malignancies of the female reproductive system. Ferroptosis, a recently identified form of programmed cell death, has garnered increasing attention in cancer research. Ubiquitin-specific peptidase 18 (USP18), a member of the deubiquitinating enzyme family, has been recognized as an oncoprotein in various cancers; however, its functional role and underlying mechanisms in EC remain largely unexplored. In this study, we found that USP18 was markedly upregulated in EC patients (n = 15, stage I; n = 4, stage II and n = 1, stage III), and elevated USP18 expression correlated with unfavorable prognosis. Functional assays demonstrated that knockdown of USP18 significantly inhibited EC cell proliferation. Moreover, USP18 silencing promoted the accumulation of lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe²⁺, thereby enhancing erastin-induced ferroptosis. In contrast, USP18 overexpression produced opposing effects. These in vitro findings were further validated in vivo, where USP18 knockdown suppressed tumor growth and promoted ferroptosis. Mechanistic investigations revealed that USP18 interacted with and deubiquitinated histone deacetylase 3 (HDAC3), thus leading to its stabilization. Subsequent rescue experiments confirmed that the tumor-promoting effects of USP18 were abrogated upon HDAC3 knockdown. Taken together, our results identify the USP18/HDAC3 axis as a key regulator of EC cell proliferation and ferroptosis suppression, underscoring the potential of USP18 as a therapeutic target in EC.