NRF2 activation resolves neuropathic pain via dual antioxidant and Na(V)1.7-Suppressive mechanisms.

Neuropathic pain remains a major clinical challenge, with current analgesics often proving ineffective and frequently refractory. Nociceptive responses are protective, while dysregulation of pain-resolving mechanisms drives the pain to be pathological. Enhancing resolving and protective signaling pathways is critical for treating neuropathic pain, yet such knowledge remains limited. In this study, we revealed the antinociceptive effects of Nrf2 in sensory neurons under both physiological and pathological conditions. Notably, insufficient activation of endogenous Nrf2 underlies the transition from acute to chronic neuropathic pain, while its activation exerts dual therapeutic effects: (1) ameliorating oxidative stress induced by peripheral nerve injury, and (2) specifically inhibiting the pathological increased Na(V)1.7 current density. Na(V)1.7 is a sodium channel with its well-established role in promoting nociceptive amplification and transmission but has failed in clinical trials by direct targeting inhibitors due to poor pharmacokinetics. Mechanistically, Nrf2 transcriptionally activated E3 ubiquitin ligase Nedd4-2, promoting Na(V)1.7 endocytosis, thereby suppressing pathological nociceptive transmission. Through combined network pharmacology screening and in silico molecular docking, we identified two NRF2-activating compounds-echinacoside and artesunate-that leverage this dual mechanism to achieve superior analgesic efficacy. These findings address critical limitations of current neuropathic pain treatments by activating new pain-resolving and protective pathways with immediate translational potential.