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

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.