Kyoungho Suk
Neuroinflammation and metabolic dysfunction converge in diverse neurological disorders, yet the molecular mechanisms linking these processes remain incompletely defined. This review integrates current evidence that the lipocalin-2 (LCN2) - pyruvate dehydrogenase kinase (PDK) axis represents a candidate mechanistic pathway, most directly established to date in diabetic peripheral neuropathy, coupling glial inflammatory activation to pathological metabolic reprogramming. LCN2, a pro-inflammatory mediator upregulated in reactive glia, drives PDK expression through two convergent mechanisms: PPARβ/δ-dependent transcription of PDK2/4, and iron-dependent HIF-1α stabilization inducing PDK1/3. PDK-mediated pyruvate dehydrogenase inhibition redirects metabolism from oxidative phosphorylation toward aerobic glycolysis, causing lactate accumulation whose functional consequences range from beneficial neuronal fuel support at physiological concentrations to potential neurotoxicity at higher, context-dependent levels (often cited around 5-10 mM), with the transition shaped by pH, tissue compartment, duration of exposure, and disease context rather than a single universal threshold. The axis operates across central and peripheral nervous system disorders with disease-specific patterns: in diabetic peripheral neuropathy, satellite glial cell LCN2 drives PPARβ/δ-PDK2-mediated lactate accumulation with Lcn2 knockout providing robust protection; in traumatic brain injury and stroke, acute astrocytic LCN2 surges are associated with secondary damage; and in Alzheimer disease, chronic microglial LCN2 elevation is associated with impaired metabolic function. Evidence for axis involvement is currently most direct and mechanistically established in diabetic peripheral neuropathy, whereas its role in traumatic brain injury, stroke, and Alzheimer disease is comparatively less characterized and remains largely correlative. Multi-level therapeutic opportunities include PDK inhibition with dichloroacetate, PPARβ/δ antagonism, LCN2 neutralization, and metabolic support strategies, although disease-specific dosing, timing, efficacy, and long-term safety (including the risk of peripheral neuropathy with dichloroacetate) require further clinical evaluation. Plasma LCN2 and hyperpolarized 13C-pyruvate magnetic resonance imaging represent promising, though still emerging, candidate biomarkers for patient stratification and target engagement monitoring. This mechanistic convergence across disorders positions the LCN2-PDK axis as a promising candidate therapeutic target, with diabetic neuropathy - where supporting evidence is currently strongest - representing the lead indication for clinical translation.