NRF2 in hypertrophic scarring: A stage-dependent redox hub poised between resolution and persistence.

Hypertrophic scarring (HTS) is a fibroproliferative outcome of deep dermal injury, reflecting failed scar resolution rather than collagen excess alone. Sustained oxidative and inflammatory signaling is a prominent feature of HTS. Reactive oxygen species (ROS) amplify TGF-β/Smad and NF-κB-linked signaling, reinforce matrix stiffening, and sustain activated fibroblasts within a mechanically loaded niche. However, how NRF2 activity changes across scar maturation-and whether it remains protective, represents a compensatory response, or supports fibroblast persistence-remains unresolved. The KEAP1-NRF2 pathway is a major redox-regulatory node, coordinating antioxidant, detoxification, metabolic, proteostatic, and anti-ferroptotic programs. We propose a testable, stage- and compartment-dependent model rather than a fixed early-to-late switch. Early injury may preferentially engage the redox-sensitive Neh2-KEAP1 arm, whereas growth-factor and mechanical signaling in established scars may increasingly influence NRF2 through the KEAP1-independent Neh6-GSK-3β/β-TrCP arm. Autophagy-linked phospho-p62 (SQSTM1) may provide a separate noncanonical but KEAP1-dependent route to NRF2 stabilization. We synthesize TGF-β/Smad-NOX4 signaling, NF-κB inflammation, p62 feedback, iron-lipid redox and ferroptosis, and mechanoredox coupling-and apply a non-ordinal engagement-to-phenotype (E2P) framework considering disease proximity, NRF2 engagement, causal dependence, scar-relevant phenotype, and replication/methodological quality. Because stage- and cell-resolved nuclear NRF2 data in human HTS are lacking, and disease-proximal evidence for persistence-permissive activity remains limited despite a recent independent gain-/loss-of-function study in human HTS fibroblasts, NRF2 is best viewed as a conditional redox hub rather than a uniformly antifibrotic switch. This framework identifies experiments needed to resolve NRF2 directionality and determine whether stage- and compartment-aware local modulation is therapeutically justified.