Integrated Proteomics Reveals Spliceosome Dysregulation and Highlights DHX9 as a TGF-β Signaling-Driven Fibrosis Hub in Endometriosis

Mengjie Yang, Yang M, Lu Zhang, Zhang L, Ding X, Xinyu Ding, Wei P, Ping Wei, Peitong Wei, Huaying Zhang, Zhang H, Chen J, Jiahao Chen, Yiqian Zhang, Zhang Y, Li D, Danyang Li, Zheng‐Yi Chen, Zhengyi Chen, Chen Z, Lin D, Dianchao Lin, Huang Z, Zhixiong Huang, Chen Q, Qionghua Chen
Journal of proteome research · 2025 · vol. 24(8) , pp. 4044–4059 · doi:10.1021/acs.jproteome.5c00122 · PMID:40638910 · W4412167235
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-07 ⓘ

This proteomic network analysis identified spliceosome dysregulation and DHX9 downregulation as key features of endometriosis, with DHX9 acting as a fibrosis hub driven by TGF-β signaling.

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This study utilized integrated proteomics and weighted gene coexpression network analysis on 22 endometrial samples to investigate molecular alterations in ectopic lesions. The researchers identified a significant downregulation of spliceosome-related proteins, highlighting DHX9 as a central hub that promotes fibrogenesis through TGF-β signaling when active. Experimental validation in both cell cultures and mouse models confirmed that knocking down DHX9 inhibits lesion growth and reduces collagen deposition by suppressing extracellular matrix organization. This paper is centrally about endometriosis — specifically the role of DHX9-mediated fibrosis and spliceosome dysregulation in the pathogenesis of ectopic lesions.

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Abstract

Endometriosis (EM) is a chronic, estrogen-dependent disease characterized by the ectopic presence of endometrial-like tissue. Despite extensive research, its molecular pathogenesis remains unclear. In this study, we conducted an integrated proteomic network analysis using 22 endometrial samples to investigate protein-level alterations in ectopic lesions. Using weighted protein coexpression network analysis (WGCNA), we identified 12 protein modules strongly associated with EM clinical traits, with the turquoise module exhibiting significant downregulation of spliceosome-related proteins in ectopic tissues. Within this module, DHX9 emerged as a top hub protein, validated as significantly downregulated in ectopic (EC) tissues at both mRNA and protein levels. Functional studies demonstrated that DHX9 knockdown in endometrial stromal cells (ESCs) inhibited proliferation and, crucially, attenuated fibrogenesis. Proteomic profiling revealed that DHX9 knockdown downregulated proteins involved in the TGF-β signaling pathway and extracellular matrix organization. Consistent with this, DHX9 knockdown in a mouse endometriosis model significantly reduced ectopic lesion growth and collagen deposition. These findings establish DHX9 as a key regulator, promoting ESC fibrogenesis via TGF-β signaling, and implicate spliceosomal dysfunction in EM pathogenesis, highlighting DHX9 as a potential therapeutic target.
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Integrated Proteomics Reveals Spliceosome Dysregulation and Highlights DHX9 as a TGF-β Signaling-Driven Fibrosis Hub in EndometriosisClick to copy article linkArticle link copied! - Mengjie YangMengjie YangClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaNational Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361102, ChinaMore by Mengjie Yang - Lu ZhangLu ZhangClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaNational Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361102, ChinaMore by Lu Zhang - Xinyu DingXinyu DingClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaMore by Xinyu Ding - Peitong WeiPeitong WeiClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaMore by Peitong Wei - Huaying ZhangHuaying ZhangClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaMore by Huaying Zhang - Jiahao ChenJiahao ChenClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaMore by Jiahao Chen - Yiqian ZhangYiqian ZhangClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaNational Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361102, ChinaMore by Yiqian Zhang - Danyang LiDanyang LiClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaMore by Danyang Li - Zhengyi ChenZhengyi ChenClinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaMore by Zhengyi Chen - Dianchao Lin*Dianchao Lin*E-mail: [email protected]Clinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaMore by Dianchao Lin - Zhixiong Huang*Zhixiong Huang*E-mail: [email protected]Clinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaMore by Zhixiong Huang - Qionghua Chen*Qionghua Chen*E-mail: [email protected]Clinical Medical Research Center for Gynecological Reproductive Health of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, ChinaNational Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361102, ChinaMore by Qionghua Chen Abstract Endometriosis (EM) is a chronic, estrogen-dependent disease characterized by the ectopic presence of endometrial-like tissue. Despite extensive research, its molecular pathogenesis remains unclear. In this study, we conducted an integrated proteomic network analysis using 22 endometrial samples to investigate protein-level alterations in ectopic lesions. Using weighted protein coexpression network analysis (WGCNA), we identified 12 protein modules strongly associated with EM clinical traits, with the turquoise module exhibiting significant downregulation of spliceosome-related proteins in ectopic tissues. Within this module, DHX9 emerged as a top hub protein, validated as significantly downregulated in ectopic (EC) tissues at both mRNA and protein levels. Functional studies demonstrated that DHX9 knockdown in endometrial stromal cells (ESCs) inhibited proliferation and, crucially, attenuated fibrogenesis. Proteomic profiling revealed that DHX9 knockdown downregulated proteins involved in the TGF-β signaling pathway and extracellular matrix organization. Consistent with this, DHX9 knockdown in a mouse endometriosis model significantly reduced ectopic lesion growth and collagen deposition. These findings establish DHX9 as a key regulator, promoting ESC fibrogenesis via TGF-β signaling, and implicate spliceosomal dysfunction in EM pathogenesis, highlighting DHX9 as a potential therapeutic target. Cited By This article is cited by 2 publications. - Zhaoyang Gao, Yihao Chen, Xiaomin Xu, Mengjie Yang, Peitong Wei, Xiaohong Que, Youyang Weng, Lemeng Wang, Lulu Ren, Xiaohong Yan, Qionghua Chen, Rongfeng Wu. The therapeutic potential of pirfenidone in alleviating fibrosis and restoring ovarian function in a novel ovarian endometriosis mouse model. Journal of Translational Medicine 2026, 24 (1) https://doi.org/10.1186/s12967-025-07648-z - Mario Palumbo, Luigi Della Corte, Maria Rotonda Conte, Giuseppe D’Angelo, Mario Ascione, Antonisia Pollio, Pierluigi Giampaolino, Giuseppe Bifulco. Is Recurrent Endometriosis a Reprogrammed Disease? Molecular Persistence Beyond Surgical Clearance. Cells 2026, 15 (10) , 951. https://doi.org/10.3390/cells15100951 Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days. Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts. The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

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Condition tags

endometriosis

MeSH descriptors

DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases DEAD-box RNA Helicases

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