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

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.