ABSTRACT Objective Ovarian clear cell carcinoma (OCCC) is prone to primary platinum resistance and has a poor prognosis in advanced stages. Understanding the mechanisms underlying chemoresistance is essential to improving treatment outcomes. This study aimed to identify and validate molecular targets linked to platinum sensitivity in OCCC and explore their clinical and biological relevance. Methods The mRNA sequencing was performed on fresh‐frozen tumor tissues from six OCCC patients (three platinum‐resistant and three platinum‐sensitive). Differentially expressed genes (DEGs) were identified using edgeR and DESeq2. A random forest model ranked candidate genes by their predictive value, and prognostic associations with progression‐free survival (PFS) and overall survival (OS) were assessed via the database of the Cancer Science Institute of Singapore (CSIOVDB). The protein expression of THBS1 was compared between groups using immunohistochemistry. Functional effects of THBS1 knockdown were assessed through CCK‐8, colony formation, wound healing, transwell assays, and tube formation assays using HUVECs. Results A total of 1592 DEGs were identified, with 43 overlapping with GSEA‐defined platinum resistance pathways. Enrichment analysis indicated significant enrichment of cancer‐related signaling pathways and biological processes were enriched in the platinum‐resistant group. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) highlighted the platelet‐associated biological processes and immune relative pathway. The immune infiltration landscape indicated a prominent immunosuppressive microenvironment in the platinum‐resistant group. THBS1 ranked highly in the random forest model and was associated with shorter PFS ( p = 0.0012) and OS ( p = 0.0046) in CSIOVDB analysis. Immunohistochemistry confirmed elevated THBS1 expression in the platinum‐resistant group ( p < 0.0001). In vitro, THBS1 knockdown reduced cell migration, invasion, angiogenesis, and cisplatin resistance. It also downregulated E‐cadherin while upregulating N‐cadherin and vimentin, suggesting EMT pathway involvement. Conclusion THBS1 promotes platinum resistance in OCCC through EMT activation and may serve as a prognostic biomarker and therapeutic target.
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