Metformin-mediated immunometabolic rewiring attenuates type I interferon-driven dendritic cell inflammation in STAT1 gain-of-function

Abstract Gain-of-function (GOF) mutations in STAT1 are associated with immune dysregulation, impaired antifungal immunity and features of chronic type I interferon pathway activation. Here, we investigated whether metformin, a widely used metabolic modulator, can attenuate inflammatory dendritic cell activation in STAT1 GOF. Using patient-derived monocyte-derived dendritic cells (moDCs) and IFN-α-stimulated healthy donor moDCs as a complementary model of IFN-driven activation, we show that metformin suppresses STAT1 GOF-associated and IFN-α-induced inflammatory features. Metformin reduced STAT1 phosphorylation, IRF7 expression, ISG transcription, NFκB-associated signaling, inflammatory cytokine production and costimulatory molecule expression, while promoting regulatory DC features. Importantly, metformin attenuated IFN-α responses both when administered before stimulation and after initiation of JAK–STAT signaling, indicating activity against established IFN-driven activation. Mechanistically, metformin induced a bioenergetically restrained metabolic state characterized by AMPK activation, reduced mitochondrial respiration and ATP production, enhanced fatty acid uptake and altered lipid trafficking. Rather than restoring oxidative energy production, metformin shifted the lipid metabolic profile toward increased abundance of pro-resolving lipid mediators. Functionally, metformin shifted IFN-α-activated moDCs toward a less inflammatory and more immunoregulatory phenotype. These findings identify metformin as an ex vivo modulator of STAT1 GOF-associated DC inflammation and support further evaluation of metabolic modulation as an adjunctive approach for type I IFN-rich inflammatory disorders.