International journal of biological macromolecules · 2025
KDELR3 and YOD1 proteins as critical endoplasmic reticulum stress mediators and potential therapeutic targets in diabetic foot ulcers: An integrated bioinformatics analysis.
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Zhou Rongbin, Zou Xiaochong, Yu Jiayin, Wang Zuheng, Lu Wenhao, Li Xiao, Wei Chunmeng, Li Xing, Wang Fubo
Аннотация
BACKGROUND: Diabetic foot ulcers (DFU) represent one of the most severe complications of diabetes mellitus and are closely associated with persistent hyperglycemia. Endoplasmic reticulum stress response proteins play critical roles in the development and progression of DFU, highlighting the urgent need for further research to identify novel biomarkers and therapeutic strategies.
METHOD: This study utilized DFU datasets from the GEO database and employed bioinformatics approaches to identify differentially expressed genes encoding endoplasmic reticulum stress (ERS) response proteins. Key regulatory proteins NCCRP1, KDELR3, BOK, and YOD1 were screened using WGCNA, machine learning algorithms, and molecular docking techniques, followed by an evaluation of their correlation with the immune microenvironment. Additionally, single-cell RNA sequencing and Mendelian randomization analysis were applied to investigate the structural and functional characteristics of these proteins in DFU pathogenesis. The expression levels of key protein biomarkers were validated using qRT-PCR.
RESULT: A total of 32 differentially expressed endoplasmic reticulum stress-related proteins associated with DFU were identified. Machine learning algorithms confirmed that NCCRP1, KDELR3, BOK, and YOD1 proteins demonstrated significant diagnostic potential as biomarkers. Immune analysis revealed associations between these stress-response proteins and immune cell infiltration, while molecular docking identified metronidazole as a promising therapeutic candidate targeting the KDELR3 and YOD1 protein structures. Experimental validation confirmed the differential expression of KDELR3 and YOD1 proteins in DFU tissues, and Mendelian randomization analysis suggested that BOK protein may be a potential causal factor in DFU development due to its structural interactions with ERS pathways.
CONCLUSION: Our study characterized specific ERS response proteins with significant diagnostic potential for DFU. These findings enhance the understanding of protein-mediated DFU pathogenesis and lay the foundation for improving diagnostic and therapeutic strategies targeting these biological macromolecules.
METHOD: This study utilized DFU datasets from the GEO database and employed bioinformatics approaches to identify differentially expressed genes encoding endoplasmic reticulum stress (ERS) response proteins. Key regulatory proteins NCCRP1, KDELR3, BOK, and YOD1 were screened using WGCNA, machine learning algorithms, and molecular docking techniques, followed by an evaluation of their correlation with the immune microenvironment. Additionally, single-cell RNA sequencing and Mendelian randomization analysis were applied to investigate the structural and functional characteristics of these proteins in DFU pathogenesis. The expression levels of key protein biomarkers were validated using qRT-PCR.
RESULT: A total of 32 differentially expressed endoplasmic reticulum stress-related proteins associated with DFU were identified. Machine learning algorithms confirmed that NCCRP1, KDELR3, BOK, and YOD1 proteins demonstrated significant diagnostic potential as biomarkers. Immune analysis revealed associations between these stress-response proteins and immune cell infiltration, while molecular docking identified metronidazole as a promising therapeutic candidate targeting the KDELR3 and YOD1 protein structures. Experimental validation confirmed the differential expression of KDELR3 and YOD1 proteins in DFU tissues, and Mendelian randomization analysis suggested that BOK protein may be a potential causal factor in DFU development due to its structural interactions with ERS pathways.
CONCLUSION: Our study characterized specific ERS response proteins with significant diagnostic potential for DFU. These findings enhance the understanding of protein-mediated DFU pathogenesis and lay the foundation for improving diagnostic and therapeutic strategies targeting these biological macromolecules.