Diabetic neuropathy's immune-metabolic network: mechanistic complexity, therapeutic challenges, and the path forward

Diabetic neuropathy (DN) is the most prevalent and debilitating complication of diabetes, with a notable absence of effective disease-modifying therapies in clinical practice. This article proposes a shift in the pathological progression of DN from focusing on "metabolic toxicity" to an integrated dysfunction within the "immune-metabolic network." We analyze the core mechanisms underlying this network and highlight how the diabetic microenvironment may drive immune cells to shift abnormally from the "Warburg effect" to "metabolic inflexibility" and "metabolic paralysis," ultimately failing to resolve inflammation and causing persistent tissue damage. Furthermore, we identify a "zero-sum game" between Schwann cells (SCs) in their roles in immune response and metabolic support. Pro-inflammatory signals trigger the collapse of the "lactate shuttle" mechanism, exposing neurons to the dual insults of "hunger" and "toxicity." At the molecular level, we highlight ZBP1 as a critical switch, sensing mitochondrial damage and is proposed to trigger the assembly of the PANoptosome complex, which forms the terminal execution pathway for neurodegenerative lesions. Given the current gap between animal models and clinical realities, we propose employing spatial transcriptomics to examine subpopulation differences between the nerve sheath and endoneurium, alongside the development of novel precision therapies targeting NLRP3 or utilizing metabolic reprogramming to restore immune repair functions. In conclusion, framing DN within the immune-metabolic network provides a new approach to overcoming the therapeutic impasse and developing truly effective interventions.