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communications biology ArticleA Nature Portfolio journalhttps://doi.org/10.1038/s42003-025-08617-4Epithelial characteristics of ovarian clearcell carcinoma at single-cell resolutionCheck for updatesQinhao Guo 1,2,9 , XiaChen 3,4,9 , RuiBi 2,5,9 , HaimingLi 2,6,9 , Meng Liu 7,9 , XingzhuJu 1,2 , Zheng Feng 1,2 , JunZhu 1,2 ,Yizhen Li 1,2 , Xin Wang 2,5 , Qiuru Huang 3 , Jiaxin Li 3 , Xiaonan Zhou 2,5 , Ying Zheng 8 , Bo Zheng7,Xiaohua Wu1,2, Jun Yu3& Hao Wen1,2Ovarian clear cell carcinoma (OCCC) represents a rare and aggressive subtype of epithelial ovariancancer with distinctive clinical and molecular characteristics. However, the identif i cation, origin, andmolecular features of the malignant epithelial cells in OCCC remain poorly studied. We establish anOCCC-associated transcriptional landscape using single-cell RNA sequencing and investigated thepropertiesofepithelialcellsintissuesfromnormalovaries,ovarianendometriosis,primaryOCCCandrecurrent OCCC to assess the status of malignant epithelial cells. We identify a specif i c subcluster ofmalignant epithelial cells and further analyze them to discover 173 candidate factors associated withOCCC. Regulon and pseudotime trajectory analyses reveal six transcription factors (TFs) and theircorresponding targets among these candidate factors, highlighting their roles in OCCC onset andreoccurrence. Through experimental validation, we conf i rm the crucial involvement of STAT3, KLF5,and TRIM28 in the proliferation and migration of OVISE cells. Silencing these three TFs also results inthe down-regulation of their associated TF targets linked to OCCC. Overall, we characterize complexmalignant-like cell populations at single-cell resolution and highlighted several TFs and their targets,providing essential resources for understanding the regulatory mechanisms underlying OCCCinitiation and recurrence.Ovarian clear cell carcinoma (OCCC) is a rare, aggressive, and chemore-sistant tumor that constitutes approximately 13% of cases of epithelialovariancancer(EOC) 1,2 .Itisconsideredanunderstudiedsubtypeofovariancancerwithanextremelypoorprognosis.Themedianoverallsurvival(OS)for recurrent OCCC (rOCCC) patients is a mere 25.3 months, and the5-year post-recurrence survival rate for rOCCC is a mere 13.2%, with overtwo-thirds of patients succumbing within 12 months and 93.1%24 months 3,4 .OCCC exhibitsdistinctclinicaland molecular features comparedtoother gynecological malignancies 2 . Although “clear cell” is a pathologyterm denoting malignant epithelial cells in OCCC, and certain factors,such as KRT7 and PAX8, have been identif i ed as playing crucial roles inOCCC diagnosis 4,5 , the unique attributes of these cell populations incomparison to other epithelial cells, as well as their origin, have not beenfully elucidated. Recently, an association between OCCC and endome-triosis has been proposed, suggesting that endometrial-type epithelialcells could serve as precursors 6 . Notably, endometriosis is associatedwith an increased risk of OCCC 7,8 . The constituents of ovarian endo-metriotic (endometrioma) cysts may inf l uence the endometrioticenvironment and contribute to the transformation of endometrioticlesions intoOCCC 9 . Recentsingle-celltranscriptomic analysisrevealed acorrelation between OCCC and endometriosis, suggesting thatendometrial-type epithelial cells may serve as precursors for thesetumors 10 .1 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. 2 Department of Oncology, ShanghaiMedical College, Fudan University, Shanghai, China.3 Institute of Reproductive Medicine, Jiangsu Province Key Laboratory in University for Inf l ammation andMolecular Drug Target, School of Medicine, Nantong University, Nantong, China.4 Center for Reproductive Medicine, Department of Obstetrics and Gynecology,Aff i liated Hospital of Nantong University, Nantong, China.5 Department of Pathology, Fudan University Shanghai Cancer Center, Fudan University,Shanghai,China.6 DepartmentofRadiology,FudanUniversityShanghaiCancerCenter,FudanUniversity,Shanghai,China. 7 StateKeyLaboratoryofReproductiveMedicine and Offspring Health, Center for Reproduction and Genetics, The Aff i liated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital,Gusu School of Nanjing Medical University, Suzhou, China.8 Department of Histology and Embryology, School of Medicine, Yangzhou University,Yangzhou, China.9 These authors contributed equally: Qinhao Guo, Xia Chen, Rui Bi, Haiming Li, Meng Liu.e-mail: bozheng@njmu.edu.cn;wu.xh@fudan.edu.cn; yujun9117@126.com; wenhao_fdc@163.comCommunications Biology| (2025) 8:1156 11234567890():,;1234567890():,;