Ding XF, Dang X, Lin S. Identification of novel therapeutic targets for diabetic neuropathy through integrated proteomics and transcriptomics approaches. World J Diabetes 2025; 16(12): 111963 [DOI: 10.4239/wjd.v16.i12.111963]
Corresponding Author of This Article
Shan Lin, MD, Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, No. 1 South Maoyuan Road, Nanchong 637000, Sichuan Province, China. dr.shanlin@foxmail.com
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Endocrinology & Metabolism
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Evidence-Based Medicine
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Dec 15, 2025 (publication date) through Dec 15, 2025
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Publication Name
World Journal of Diabetes
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1948-9358
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Ding XF, Dang X, Lin S. Identification of novel therapeutic targets for diabetic neuropathy through integrated proteomics and transcriptomics approaches. World J Diabetes 2025; 16(12): 111963 [DOI: 10.4239/wjd.v16.i12.111963]
World J Diabetes. Dec 15, 2025; 16(12): 111963 Published online Dec 15, 2025. doi: 10.4239/wjd.v16.i12.111963
Identification of novel therapeutic targets for diabetic neuropathy through integrated proteomics and transcriptomics approaches
Xue-Feng Ding, Xin Dang, Shan Lin
Xue-Feng Ding, Department of Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
Xin Dang, Shan Lin, Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
Co-first authors: Xue-Feng Ding and Xin Dang.
Author contributions: Ding XF and Dang X mainly performed data extraction and statistical analysis, they contributed equally to this article, they are the co-first authors of this manuscript; Ding XF and Lin S designed the study and wrote the draft of this manuscript; Lin S revised this manuscript; and all authors are involved in data correction.
Supported by the Key Project of the Affiliated Hospital of North Sichuan Medical College, No. 2023ZD008; the Project of the Doctoral Initiation Fund, No. 2023GC002; Scientific Research and Development Program Project, No. 2024PTZK008; Sichuan Province Clinical Key Specialty Construction Project, No. 2023GZZKP002; Science and Technology Project of Nanchong, No. 22SXQT0364; and Research Development Plan Project of Affiliated Hospital of North Sichuan Medical College, No. 2024MPZK003.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Shan Lin, MD, Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, No. 1 South Maoyuan Road, Nanchong 637000, Sichuan Province, China. dr.shanlin@foxmail.com
Received: July 23, 2025 Revised: September 17, 2025 Accepted: November 3, 2025 Published online: December 15, 2025 Processing time: 145 Days and 12.1 Hours
Abstract
BACKGROUND
Diabetic neuropathy (DN) is a progressive disorder with limited effective treatment options.
AIM
To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.
METHODS
A comprehensive analytical framework was developed to identify multi-omics biomarkers of DN. Protein-protein interaction network and Gene Ontology analyses were performed to explore the biological functions of biomarkers. Tier 1 target proteins were further analyzed. Candidate drug prediction and molecular docking studies were conducted to identify potential treatments while assessing the side effects of key target proteins. The mediation of immune cells in the association between proteins and DN was examined through two-step network Mendelian randomization (MR) analysis.
RESULTS
Nine DN-associated proteins were identified by analyzing protein quantitative trait loci from extensive genome-wide association study data. BTN3A1 and MICB were confirmed using MR, summary data-based MR, and colocalization analyses. Of the nine, HSPA1B, PSMB9, BTN3A1, SCGN, NOTUM, and MICB showed negative associations with DN, whereas WARS, BRD2, and CSNK2B were positive. Gene Ontology analysis indicated enrichment in inflammatory response and neuronal injury pathways. BTN3A1 and MICB were identified as Tier 1 targets. Drug prediction and molecular docking analyses indicated cyclosporin A as a potential therapeutic candidate. Two-step network MR analysis showed that MICB mediated DN through human leukocyte antigen-DR++ monocytes. These integrated findings point to an immune-mediated mechanism with translational potential and nominate BTN3A1 and MICB for focused functional validation.
CONCLUSION
Our integrated multi-omics approach identified two promising therapeutic targets for DN, laying the groundwork for new treatment strategies and enhancing our understanding of MICB’s role in DN.
Core Tip: This integrated multi-omics study identified nine diabetic neuropathy (DN)-associated plasma proteins, validated across independent datasets. BTN3A1 and MICB emerged as top-tier therapeutic targets, robustly confirmed via Mendelian randomization (MR), summary-data-based MR, and colocalization analyses. Functional enrichment links these proteins to inflammation and neuronal injury. Crucially, cyclosporine A was predicted as a potential repurposed drug candidate targeting MICB. Furthermore, two-step network MR revealed MICB mediates DN risk specifically through human leukocyte antigen-DR++ monocyte abundance, providing a novel mechanistic immune pathway. This work unveils BTN3A1 and MICB as promising targets and elucidates MICB’s immune-mediated role in DN pathogenesis.
