This study investigated whether the endogenous metabolite flavin adenine dinucleotide (FAD) acts as a suppressor of cytosolic nucleic acid sensors — cGAS (DNA sensor) and RIG-I (RNA sensor) — and examined the physiological and immunological consequences of FAD deficiency via FLAD1 (FAD synthase) ablation in the context of sterile inflammation, cellular senescence, and viral infection.
FAD directly bound to cGAS and RIG-I catalytic pockets, suppressing their activity and downstream IFN-I signaling. FLAD1 depletion lowered FAD levels, removed inhibitory control over both sensors, enhanced innate immune responses, and protected mice from viral infection; conversely, FAD deficiency exacerbated autoinflammation and cellular senescence.
Findings are largely mechanistic and preclinical (mouse models); translation to human inflammatory or antiviral contexts is not yet demonstrated. The study does not address tissue-specific FAD dynamics or long-term effects of FLAD1 depletion on host fitness beyond viral protection.
FAD and the FLAD1 enzyme represent a novel immunometabolic axis that could be targeted to tune innate immune responses — boosting antiviral immunity or dampening autoinflammation. Clinicians should watch for therapeutic strategies modulating FAD biosynthesis in inflammatory diseases and infection.
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