The pivotal role of immunometabolism in diabetic neuropathy and its potential therapeutic strategies

Diabetic peripheral neuropathy (DPN) is a prevalent and severely disabling complication of diabetes mellitus characterized by complex pathophysiological mechanisms. Beyond the metabolic disorder induced by glucolipotoxicity, DPN represents an immunometabolic dysregulation arising from the interaction between metabolic abnormalities and immune imbalance. This review comprehensively encapsulates recent advances in the understanding of DPN through the lens of immunometabolism. Initially, classical pathophysiological mechanisms are discussed, demonstrating that persistent hyperglycemia and lipotoxicity activate the polyol pathway, promote advanced glycation end products formation, and lead to mitochondrial dysfunction, which collectively inflict structural and functional damage to neurons, Schwann cells, and neurovascular units. Furthermore, neuroinflammation in DPN transcends the peripheral nerve-dorsal root ganglion-spinal cord axis, with immune cell activation and inflammatory microenvironment formation directly perpetuating clinical symptoms such as hyperalgesia and hypoesthesia. This review further delves into the molecular basis of immunometabolic dysregulation, exploring oxidative stress from excessive reactive oxygen species, nitrative stress from nitric oxide signaling imbalance, and cytokine-mediated inflammatory amplification involving TNF-α, IL-1β, and IL-6. The role of intestinal dysbiosis in shaping systemic immune responses through metabolite anomalies also receives attention, contributing to the neuropathic pathology. These interconnected pathways foster a pathological positive feedback loop. In addition, the spatiotemporal dynamics of immune cells like monocytes/macrophages, T cells, B cells, microglia, and mast cells in the context of DPN are scrutinized, highlighting metabolic reprogramming and pro-inflammatory phenotypic shifts under hyperglycemic conditions. The review elucidates the complex crosstalk network between immune cells and non-immune cells, such as Schwann cells and vascular endothelial cells, which centralizes neuroinflammation regulation in DPN. Finally, potential therapeutic strategies focusing on immunometabolism are summarized, offering prospects for clinical translation. This immunometabolic perspective proves crucial in refining intervention regimens for DPN. In conclusion, immunometabolic dysregulation underpins the pathological progression of DPN, providing a comprehensive theoretical foundation for understanding its complex pathology and developing targeted therapeutic strategies.