Yuan XJ, Zhang ZC, Li J, Ye SD, Zhou W. Identification and mechanistic insights of ubiquitin-proteasome system and pyroptosis-related biomarkers in type 2 diabetes mellitus. World J Diabetes 2025; 16(8): 104879 [PMID: 40837339 DOI: 10.4239/wjd.v16.i8.104879]
Corresponding Author of This Article
Wan Zhou, PhD, Chief Physician, Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Hefei 230001, Anhui Province, China. zwan@ustc.edu.cn
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Endocrinology & Metabolism
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Basic Study
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Aug 15, 2025 (publication date) through Feb 27, 2026
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World Journal of Diabetes
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Yuan XJ, Zhang ZC, Li J, Ye SD, Zhou W. Identification and mechanistic insights of ubiquitin-proteasome system and pyroptosis-related biomarkers in type 2 diabetes mellitus. World J Diabetes 2025; 16(8): 104879 [PMID: 40837339 DOI: 10.4239/wjd.v16.i8.104879]
World J Diabetes. Aug 15, 2025; 16(8): 104879 Published online Aug 15, 2025. doi: 10.4239/wjd.v16.i8.104879
Identification and mechanistic insights of ubiquitin-proteasome system and pyroptosis-related biomarkers in type 2 diabetes mellitus
Xiao-Jing Yuan, Zi-Chen Zhang, Jie Li, Shan-Dong Ye, Wan Zhou
Xiao-Jing Yuan, Zi-Chen Zhang, Shan-Dong Ye, Wan Zhou, Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Jie Li, Department of Endocrinology, Anhui Provincial Hospital, Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
Co-first authors: Xiao-Jing Yuan and Zi-Chen Zhang.
Author contributions: Zhou W designed the researchand wrote the manuscript; Yuan XJ and Zhang ZC collected and analyzed the data, conducted the experiments and interpreted the experimental results; Yuan XJ and Li J performed the statistical analyses; Ye SD reviewed and edited the manuscript; Zhou W is the guarantor of this work; All authors read and approved the final version of the manuscript. Yuan XJ and Zhang ZC have contributed equally to this work.
Supported by National Natural Science Foundation of China, No. 82270863 and No. 82470849; Major Project of Anhui Provincial University Research Program, No. 2023AH040400; Joint Fund for Medical Artificial Intelligence, No. MAI2023Q026; and the Project of Health Commission Scientific Research in Anhui Province, No. AHWJ2024Aa20477.
Institutional review board statement: This study received approval from the Ethics Committee of The First Affiliated Hospital of USTC.
Institutional animal care and use committee statement: This study received approval from the Animal Care and Research Advisory Committee of the First Affiliated Hospital of University of Science and Technology of China.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
ARRIVE guidelines statement: This study received approval from the Animal Care and Research Advisory Committee, following ARRIVE guidelines.
Data sharing statement: The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Corresponding author: Wan Zhou, PhD, Chief Physician, Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Hefei 230001, Anhui Province, China. zwan@ustc.edu.cn
Received: January 5, 2025 Revised: March 23, 2025 Accepted: May 26, 2025 Published online: August 15, 2025 Processing time: 222 Days and 0.4 Hours
Abstract
BACKGROUND
Pyroptosis and ubiquitination have been identified as key processes influencing the pathogenesis of diabetes mellitus (DM).
AIM
To investigate the genes associated with the ubiquitin-proteasome system (UPS) and pyroptosis in type 2 DM (T2DM), and elucidate their mechanisms of action in T2DM.
METHODS
The datasets GSE76894, GSE41762, and GSE86469 were utilized in this study. UPS-related genes (UPSGs) and pyroptosis-related genes (PRGs) were obtained from existing literature. Differential expression analysis was performed to identify differentially expressed genes (DEGs). DEGs were intersected with UPSGs and PRGs to identify differentially expressed UPSGs and PRGs. Ubiquitin-pyroptosis-related biomarkers were determined using Spearman’s correlation, t-tests, and receiver operating characteristic curve analysis. Pathway enrichment of biomarkers was assessed using Gene Set Enrichment Analysis (GSEA). Single sample GSEA (ssGSEA) and Spearman’s correlation were used to analyze the relationship between biomarkers and immune cells. A competitive endogenous RNA network was constructed. Subsequently, drugs related to the biomarkers were identified and a gene-drug network was established. In dataset GSE86469, single-cell sequencing was utilized to determine cell types. Finally, the expression levels of biomarkers were validated through quantitative PCR (qPCR) and western blot analysis.
RESULTS
A total of 581 DEGs were identified in GSE76894. Four genes [ATP binding cassette subfamily C member 8 (ABCC8), retinol binding protein 4 (RBP4), Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1), and solute carrier family 34 member 2 (SLC34A2)] were identified as ubiquitin-pyroptosis-related biomarkers in T2DM, based on consistent expression trends and significant differences in GSE76894 and GSE41762. These biomarkers were enriched in oxidative phosphorylation and mitogen-activated protein kinase signaling pathways, which are relevant to DM. ssGSEA revealed significant differences in the enrichment scores of nine immune cell types between groups. A total of 17 microRNAs (miRNAs) and 36 long non-coding RNAs (lncRNAs) were identified, forming numerous miRNA-lncRNA interactions. Additionally, 22 drugs related to the biomarkers, such as gliclazide and tretinoin, were identified. In GSE86469, eight cell types, including alpha and beta cells, were characterized. qPCR and western blot analysis confirmed that the expression trends of RASGRF1 and SLC34A2 were consistent with the findings in GSE76894.
CONCLUSION
This study identified four ubiquitin-pyroptosis-related biomarkers (ABCC8, RBP4, RASGRF1, and SLC34A2) in T2DM through bioinformatics analysis, providing novel insights into the diagnosis and treatment of T2DM.
Core Tip: This study identified four ubiquitination and pyroptosis-associated biomarkers (ATP binding cassette subfamily C member 8, retinol binding protein 4, Ras protein-specific guanine nucleotide-releasing factor 1, and solute carrier family 34 member 2) in type 2 diabetes mellitus (T2DM) through integrated bioinformatics analysis, establishing a potential mechanistic link between ubiquitin-proteasome system dysregulation and pyroptosis in T2DM pathogenesis. These biomarkers were enriched in oxidative phosphorylation and mitogen-activated protein kinase signaling pathways, and modulated immune cell infiltration. Our research discovered possible drug candidates and a gene interaction network linked to RNA competition, which may aid in detecting and treating type 2 diabetes.
