Inflammation‐Regeneration Axis of Dental Pulp Stem Cells: Wnt/NF‐κB Crosstalk

BACKGROUND: Inflammation critically determines dental pulp regenerative outcomes, with dental pulp stem cells (DPSCs) orchestrating tissue homeostasis through differentiation, self-renewal and immunomodulation processes dynamically regulated by Wnt/β-catenin and NF-κB signaling crosstalk. Given the rising therapeutic potential of Wnt-targeted interventions in dental tissue engineering, elucidating these molecular interactions under pathological conditions is essential for developing regenerative therapeutics capable of simultaneously promoting reparative dentinogenesis while resolving inflammatory insults. OBJECTIVES: This perspective review aims to: (1) critically evaluate existing literature on lipopolysaccharide (LPS)-mediated modulation of dental pulp stem cell (DPSC) fate, addressing inconsistencies in LPS concentrations, bacterial sources and inflammatory models; (2) identify methodological gaps in current standardisation and elucidate molecular mechanisms governing Wnt/NF-κB signaling crosstalk in DPSCs under acute versus chronic inflammatory conditions; and (3) assess the therapeutic potential of GSK3β inhibitors and exosome-based interventions for dentine-pulp regeneration. METHODOLOGY: A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus and Web of Science Core Collection for publications through November 2025. Search strategies combined four thematic domains: (1) cell populations ("dental pulp stem cell" OR "DPSC"); (2) signaling pathways ("Wnt" OR "β-catenin" AND "NF-κB" OR "crosstalk"); (3) biological processes ("odontogenic differentiation" OR "immunomodulation" OR "macrophage polarization"); (4) inflammatory context ("pulpitis" OR "inflammation" OR "LPS"). Articles were screened for relevance to Wnt/NF-κB interactions in dental pulp regeneration under inflammatory conditions. RESULTS AND DISCUSSION: Evidence demonstrates context-dependent Wnt/NF-κB crosstalk in DPSC fate specification. Low-dose LPS (< 1 μg/mL) stimulates reparative responses through coordinated Wnt/NF-κB activation, whereas sustained high-dose exposure (> 1 μg/mL) suppresses Wnt signaling via NF-κB-driven DKK1 upregulation, attenuating differentiation capacity. While no direct evidence links Wnt/NF-κB crosstalk to DPSC self-renewal, both pathways independently maintain stemness. Critically, DPSCs and macrophages exhibit reciprocal regenerative interactions: DPSC-derived Wnt3a polarises macrophages toward the anti-inflammatory M2 phenotype, while M2-secreted Wnt7b enhances DPSC odontogenic differentiation by suppressing NF-κB expression. However, standardised inflammation models remain lacking, hindering comprehensive elucidation of context-dependent mechanisms. Developing such models would clarify how inflammation temporally and spatially influences regenerative outcomes across clinical scenarios.