NLRP3 autophagic degradation disruption in melanocytes contributes to vitiligo development.
This study investigated how dysregulation of the NLRP3 inflammasome in melanocytes contributes to vitiligo pathogenesis. Using skin samples from vitiligo patients and a melanoma-Treg-induced vitiligo mouse model, the researchers found that NLRP3 expression is significantly elevated in vitiligo melanocytes. Mechanistically, they identified that decreased expression of the E3 ubiquitin ligase β-TrCP1 in vitiligo melanocytes reduces K27-linked ubiquitination of NLRP3, weakening its interaction with the autophagy receptor NDP52. This disrupts selective autophagic clearance of NLRP3, allowing it to hyperactivate inflammatory and pyroptotic pathways—including GSDMD pore formation and IL-1β release—ultimately destroying melanocytes. Genetic knockout of NLRP3 in mice alleviated vitiligo progression. As a potential therapeutic approach, the authors developed lysine-proline-valine (KPV)-modified deformable liposomes carrying Nlrp3 shRNA, which achieved melanocyte-targeted NLRP3 knockdown and reduced vitiligo development in mice. Key limitations include reliance primarily on a mouse model, limited human mechanistic validation, and the therapeutic intervention being tested only in animals, leaving clinical translation unestablished.