Melatonin suppresses ILC2-driven airway hyperreactivity via glutathione-dependent metabolic reprogramming

Allergic asthma is characterized by type 2 inflammation and overnight worsening of symptoms, yet dynamic fluxes in cellular metabolic profiles driving time-of-day variation remain poorly defined. Group 2 innate lymphoid cells (ILC2s) are central mediators of airway hyperreactivity. We identify melatonin as a previously unrecognized regulator of ILC2 metabolism and function. In murine models of allergic airway inflammation, melatonin reduced eosinophilia, type 2 cytokine production, and airway hyperreactivity without altering ILC2 abundance. Mechanistically, melatonin acted independently of canonical melatonin receptors and instead reprogrammed ILC2 metabolism toward pentose phosphate pathway activity, enhancing NADPH generation and NRF2-dependent glutathione accumulation. Metabolic profiling, loss-of-function approaches, and pharmacologic activation studies demonstrated that NRF2 is both necessary and sufficient to restrain ILC2 effector function. Importantly, primary human ILC2s exhibited conserved NRF2 activation, glutathione accumulation, and reduced type 2 cytokine production in response to melatonin, underscoring clinical relevance. Together, these findings identify the melatonin-NRF2-glutathione axis as a metabolic checkpoint regulating innate type 2 immunity and suggest that therapeutic targeting of redox metabolism may represent a strategy for modulating airway inflammation in allergic asthma.