Diabetic Peripheral Neuropathy: Molecular Staging, Risk Factors, Therapeutics, and Emerging Trends

ABSTRACT The escalating global burden of diabetes has led to a rise in diabetic peripheral neuropathy (DPN) that is characterized by significant heterogeneity, with its various subtypes exhibiting distinct yet overlapping clinical manifestations and pathogenic drivers. This complexity obscures a unified mechanistic understanding and hinders the development of precise subtype‐specific therapeutic strategies. This review reframed DPN into a unified model centered on three progressive pathogenic stages: metabolic dysregulation, chronic inflammation, and overt neuronal damage. Within this framework, six DPN subtypes—hyperglycemia‐driven, dyslipidemia‐driven, inflammation, dysvascularity‐driven, small‐fiber DPN, and large‐fiber DPN—were classified into these identified mechanistic triads that converge to redox imbalance. Risk factors across genetic, epigenetic, and phenotypic levels were identified, emphasizing metabolic drivers as key initiators of neuroinflammatory and neurodegenerative cascades. Current therapeutic strategies were evaluated according to their alignment with specific pathogenic stages, ranging from metabolic regulation and anti‐inflammatory approaches to nerve repair. Furthermore, cold atmospheric plasma (CAP) was introduced as a novel multimodal intervention capable of simultaneously targeting all three pathological phases through redox modulation, offering a promising avenue for precision medicine in DPN management. This integrated staging model not only clarified the mechanistic continuum of DPN but also facilitated the development of targeted stage‐specific therapeutic strategies.