Redox Mechanisms and NRF2 Signaling in Trigeminal Neuralgia: From Evidence to Network-Guided Prioritization of Candidate Herbal Medicines

Trigeminal neuralgia is classically explained by neurovascular compression, focal demyelination, and pathological hyperexcitability, but emerging evidence suggests that oxidative stress may form a modifiable molecular layer within this framework. Cerebrospinal fluid from patients contains elevated lipid-peroxidation products capable of activating transient receptor potential ankyrin 1 (TRPA1), a redox-sensitive pain-sensing ion channel, while experimental trigeminal injury studies show that manipulation of nuclear factor erythroid 2-related factor 2 (NRF2) signaling and its downstream effector heme oxygenase-1 can reduce allodynia, oxidative injury, pyroptosis, and satellite glial-cell activation. This review organizes trigeminal redox biology around NRF2-centered antioxidant signaling, in which Kelch-like ECH-associated protein 1 regulates NRF2-dependent transcription through antioxidant response elements, and examines its intersection with TRPA1 and the voltage-gated sodium channel Nav1.7. We then evaluate plant-derived compounds and herbal medicines against this framework. The available evidence remains asymmetric: compounds tested in trigeminal models rarely include causal redox endpoints, whereas compounds with strong NRF2-linked analgesic evidence have largely been studied outside the trigeminal system. A limited multiscale network-pharmacology case study prioritizes Cistanchis Herba as a redox-relevant herbal candidate. Independent pharmacological evidence further identifies its constituent echinacoside as the primary translational compound for trigeminal evaluation, whereas hydroxytyrosol is better regarded as a secondary metabolite-exposure hypothesis. These findings define testable hypotheses rather than established treatments and support experimental evaluation of NRF2-targeted, plant-derived adjunctive strategies in trigeminal neuropathic pain.