Paeoniflorin as a candidate disease-modifying therapy for diabetic peripheral neuropathy: mechanisms, exposure challenges, and translational priorities

Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes and remains largely treated with symptomatic analgesics (e.g., pregabalin, duloxetine) that do not reverse nerve fiber loss or demyelination, underscoring the need for disease-modifying therapies. Paeoniflorin (PF), a plant-derived monoterpene glycoside metabolite from Paeonia spp., shows multitarget activity relevant to DPN pathophysiology in preclinical studies, including activation of Nrf2/HO-1 antioxidant signaling, suppression of TLR4/NF-κB-driven neuroinflammation, support of neurotrophic/repair pathways (e.g., BDNF/TrkB) for axonal regeneration and remyelination, and modulation of microvascular pathways (e.g., HIF-1α/VEGF) linked to endoneurial perfusion. We critically appraise this evidence and highlight key translational constraints: very low oral bioavailability and poor intestinal permeability, extensive presystemic biotransformation (microbiome-mediated hydrolysis and CYP-mediated metabolism) with unresolved “active species” (parent PF versus metabolites), and limited DPN-relevant pharmacokinetics, particularly the lack of peripheral nerve/DRG exposure measurements aligned with pharmacodynamic endpoints. Although formulation and delivery approaches may improve exposure, PF-specific validation in DPN models is currently limited and should be distinguished from platform-level concepts. Finally, because DPN patients frequently experience polypharmacy, a clinically meaningful safety narrative requires systematic assessment of CYP/transporter-mediated drug–drug interaction potential. Priority next steps include integrated PK–PD studies with nerve/DRG distribution, metabolite-resolved exposure–activity linkage, PF-specific delivery validation using disease-modifying endpoints beyond pain behavior, and standardized DDI screening to support trial design.