UBTD1 Drives Ovarian Cancer Progression via Mutation‐Associated Alterations, Stromal Microenvironment Remodeling, and TNF/AP‐1 Signaling

Abstract

Background The ubiquitin domain‐containing protein 1 (UBTD1) is involved in protein homeostasis and cell cycle regulation, and emerging evidence suggests its role in tumor biology. However, its function in ovarian cancer (OC) remains unclear. OC is highly lethal due to late diagnosis, metastasis, and platinum resistance. This study is aimed at investigating the role of UBTD1 in OC by integrating single‐cell transcriptomics, mutation and HRD‐related analyses, tumor microenvironment evaluation, and experimental validation. Methods We examined UBTD1 expression, prognosis, somatic mutation features, and immune microenvironment characteristics utilizing public databases, such as the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Single‐cell RNA‐seq data were analyzed using Seurat, hdWGCNA, and CopyKAT to characterize UBTD1‐associated malignant‐cell states and inferred CNV burden. Based on the median UBTD1 expression, TCGA‐OV samples were divided into high and low expression groups to compare mutation spectra, DNA repair pathway activity, stromal scores, and immune cell infiltration. Functional assays were performed in A2780 and SK‐OV‐3 cell lines following lentiviral shRNAs‐mediated UBTD1 knockdown. RNA sequencing and rescue experiments were used to explore downstream pathways. Results Integrated single‐cell and TCGA‐OV analyses revealed that UBTD1‐low tumors were enriched for genomic instability–related features, including increased inferred CNV burden and higher tumor mutation burden. By comparison, UBTD1‐high tumors showed increased stromal scores and modest enrichment of selected immune‐cell populations, including macrophages and neutrophils. Experimentally, UBTD1 was upregulated in OC and associated with poor prognosis. UBTD1 knockdown inhibited malignant phenotypes, enhanced cisplatin sensitivity, promoted apoptosis, and suppressed TNF/AP‐1/FOS–related signaling. FOS overexpression partially reversed the effects of UBTD1 silencing. Conclusions UBTD1 expression defines distinct mutation and microenvironmental states in OC and functionally promotes malignant phenotypes, potentially through TNF/AP‐1/FOS–related signaling.