NRF2 pathway activation to reduce mutant huntingtin aggregates and oxidative stress in HD

NRF2 activation addresses the proteostasis collapse and oxidative stress in HD through transcriptional upregulation of antioxidant and phase II detoxification genes. Omaveloxolone's FDA approval for Friedreich's ataxia provides regulatory precedent, and zQ175 knock-in mice represent a more translationally relevant model than aggressive R6/2 mice. Major safety concerns include cardiac toxicity (BEACON trial termination), narrow therapeutic window, and potential tumor promotion with chronic activation. The hypothesis suffers from weak preclinical data and unclear mechanistic links between NRF2 and mHTT aggregation reduction.