{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:29:49Z","timestamp":1788449389246,"version":"build-2803163510"},"reference-count":84,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 \u201cmetabolic toxicity\u201d to an integrated dysfunction within the \u201cimmune-metabolic network.\u201d We analyze the core mechanisms underlying this network and highlight how the diabetic microenvironment may drive immune cells to shift abnormally from the \u201cWarburg effect\u201d to \u201cmetabolic inflexibility\u201d and \u201cmetabolic paralysis,\u201d ultimately failing to resolve inflammation and causing persistent tissue damage. Furthermore, we identify a \u201czero-sum game\u201d between Schwann cells (SCs) in their roles in immune response and metabolic support. Pro-inflammatory signals trigger the collapse of the \u201clactate shuttle\u201d mechanism, exposing neurons to the dual insults of \u201chunger\u201d and \u201ctoxicity.\u201d 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1804076","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:21:17Z","timestamp":1776918077000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Diabetic neuropathy\u2019s immune-metabolic network: mechanistic complexity, therapeutic challenges, and the path forward"],"prefix":"10.3389","volume":"17","author":[{"given":"Wenjuan","family":"Sun","sequence":"first","affiliation":[{"name":"Jilin Provincial People\u2019s Hospital","place":["Changchun, China"]},{"name":"Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunpeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Jilin 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