痛性糖尿病周围神经病变的营养感知机制:基于背根神经节多组学测序发现枢纽miRNA-mRNA调控网络OA

Objective Painful diabetic peripheral neuropathy(PDPN)is a common and debilitating complication of diabetes mellitus,with complex clinical manifestations and pathogenesis.From the perspective of PDPN progression,how nutrient sensing alters gene transcription represents a scientifically significant question worthy of investigation.However,the underlying molecular mechanisms,particularly the association between post-transcriptional regulatory processes in the dorsal root ganglia(DRG)and PDPN,remain poorly understood.Therefore,this study employed an integrated multi-omics approach to comprehensively profile the miRNA and mRNA expression landscape and analyze their regulatory networks in the DRG of a well-established rat model of PDPN.Methods Eighteen male SD rats(aged 4 to 5 weeks,weighing 90 to 100 g)were randomly divided into a vehicle control group and a PDPN group.The rat model of PDPN was established by an intraperitoneal injection of streptozotocin(STZ).The DRG tissues from L4 to L6 were harvested from both groups(n=3 per group)for high-throughput sequencing of miRNAs and mRNAs.Bioinformatic analyses were performed to identify differentially expressed miRNAs(DEmiRs)and mRNAs(DEGs),followed by GO and KEGG enrichment analyses.An integrated miRNA-mRNA regulatory network was constructed.Preliminary validation was performed using RT-qPCR,with subsequent comparative analysis with relevant human-derived data.Results A total of 11 significantly upregulated and 7 significantly downregulated DEmiRs(|log2FC|>1,P<0.05),along with 416 upregulated and 110 downregulated DEGs(|log2FC|>1,P<0.05),were identified.KEGG pathway analysis revealed that DEGs were significantly enriched in the pathways closely related to pain and diabetic metabolism(threshold P<0.05),such as neuroactive ligand-receptor interaction and lipid metabolism.Through construction of the miRNA-mRNA regulatory network,the results indicated that Ms4a2,Itgax,Wnt3,Tnn,and their upstream miRNAs may serve as core hubs regulating PDPN progression.Conclusion This study provides an initial systematic depiction of the miRNA-mRNA interaction network in the DRG of a PDPN model,demonstrating that Ms4a2,Itgax,Wnt3,Tnn,and their upstream miRNAs may modulate nutrient-sensing mechanisms involved in PDPN progression.Multiple potential therapeutic targets for PDPN are identified,including let-7i-5p,miR-9a-5p,miR-543-5p,miR-199a-5p,miR-324-5p,miR-702-3p,Ikzf3,Klhl6,Igsf6,Tmc8,Tmc1,Lmx1a,Cldn16,Vwc2,and Cyp2c23.Importantly,sphingolipid metabolism is regarded as a key pathway likely connecting metabolic alterations to the development of PDPN.Our work preliminarily explores the nutrient-sensing mechanisms underlying PDPN progression from a novel perspective.