Identification and verification of key genes related to oxidative stress in type 2 diabetes and screening of candidate drugs from Traditional Chinese Medicine

OBJECTIVE: To identify oxidative stress (OS)-related genes involved in type 2 diabetes mellitus (T2DM) and screen potential Traditional Chinese Medicine (TCM) candidates for therapeutic use.METHODS: Gene expression data from the GSE23343 dataset were obtained from the Gene Expression Omnibus (GEO) database.Differentially expressed genes (DEGs) between healthy and T2DM patients were identified.Weighted gene co-expression network analysis (WGCNA) was performed to select modules highly correlated with clinical traits, and core genes within these modules were identified.OS-related genes were retrieved from the GeneCards database, and the overlapping DEGs, WGCNA genes, and OS-related genes were considered as hub genes in OS-related T2DM.These hub genes were validated in GSE15653 dataset.Potential TCMs were identified by mapping the hub genes to the Coremine Medical database.In vivo validation was performed using a T2DM rat model established by a high-fat diet and streptozotocin injection.The effects of Wedelolactone were evaluated by assessing gene expression via real-time quantitative reverse transcription PCR (qRT-PCR) and Western blot, alongside metabolic and liver function parameters, including fasting blood glucose, glycated serum protein, insulin resistance, and lipid profiles.RESULTS: A total of 394 DEGs (136 up-regulated and 258 down-regulated DEGs.) were identified in the GSE23343 cohort.WGCNA results showed that the turquoise module (cor = -0.56,P = 0.02) and the brown module (cor = 0.66, P = 0.004) were the most correlated with T2DM.Six hub genes [interleukin 33 (IL33), S100 calcium binding protein A8 (S100A8), Golgi membrane protein 1 (GOLM1), small nuclear ribonucleoprotein U1 subunit 70 (SNRNP70), hepatocyte growth factor activator (HGFAC), and oxidative stress induced growth inhibitor 1 (OSGIN1)] were identified, with IL33, S100A8, and GOLM1 being up-regulated, and SNRNP70, HGFAC, and GOLM1 being down-regulated.These genes distinguished T2DM from healthy controls with AUC values greater than 0.8.Experimental verification using a T2DM rat model confirmed the expression patterns of the hub genes.In vivo data demonstrated that Wedelolactone significantly reduced oxidative stress, inflammation hepatic lipid accumulation, and improved metabolic parameters such as fasting blood glucose, glycated serum protein, and insulin resistance.CONCLUSION: These findings highlight the critical roles of IL33, S100A8, GOLM1, SNRNP70, HGFAC, and OSGIN1 as biomarkers in OS-related T2DM and suggest that Wedelolactone may be a promising TCM-based therapeutic candidate for T2DM.