Flavin adenine dinucleotide is an endogenous suppressor for cytosolic DNA and RNA sensors to modulate innate immunity

Yao Wang, Yanyan Shen, Na Wang, Qing Xia, Weina Zhang

1. 01

   FAD binds directly into the catalytic pockets of both cGAS and RIG-I, blocking cGAMP production and ATPase activity respectively

2. 02

   FAD acts at the sensor level rather than downstream in the signalling cascade

3. 03

   Physiologically FAD prevents self-nucleic-acid-induced sterile inflammation and maintains immune homeostasis

4. 04

   FAD deficiency via FAD synthase (FLAD1) ablation exacerbated autoinflammation AND cellular senescence

5. 05

   During viral infection, reduced FLAD1 activity lowers FAD, releasing the brake and amplifying type-I interferon signalling

6. 06

   FLAD1 depletion strengthened innate immune response and protected mice from viral infection

Study Design

Preclinical Study

Sample Size

Not reported

Study Duration

Not applicable (mechanistic)

Methodology

Screen of endogenous metabolites for inhibition of interferon induction after cytosolic nucleic-acid exposure; binding, mutation, colocalisation microscopy and structure-prediction assays; FLAD1 genetic ablation in cells and mice; viral challenge experiments.

Limitations

Mechanistic cell and mouse work only — no human data. Critically, the causal manipulation is intracellular FLAD1-dependent FAD availability, NOT oral riboflavin supplementation; this study provides no evidence that B2 supplements alter inflammaging in humans. The therapeutic window is also constrained in both directions: raising FAD would be expected to blunt antiviral type-I interferon at the same time as it damps sterile inflammation.