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

  • Immunity. 2026 Jul 13:S1074-7613(26)00261-X. doi: 10.1016/j.immuni.2026.06.010.
Yao Wang  1 ,  Yanyan Shen  1 ,  Jiayu Liu  1 ,  Qi Qi  1 ,  Yue Guo  1 ,  Yunying Wang  1 ,  Boyang Xie  1 ,  Chunyan Yan  1 ,  Yanhong Liu  1 ,  Zhi Jin  1 ,  Ruibo Wang  1 ,  Aiping Cao  1 ,  Juncheng Li  1 ,  Zengqing Song  1 ,  Jing Chen  1 ,  Qiuying Han  1 ,  Yingjie Zhu  1 ,  Kun Zhang  2 ,  Taixia Wang  2 ,  Tao Li  1 ,  Xin Pan  1 ,  Xinhua He  3 ,  Tao Zhou  1 ,  Ailing Li  1 ,  Xuemin Zhang  1 ,  Na Wang  4 ,  Qing Xia  5 ,  Weina Zhang  6
Affiliations
  • 1. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis, NCBA), Beijing 100039, China.
  • 2. Department of Laboratory Medicine and Department of Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 3. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis, NCBA), Beijing 100039, China; State Key Laboratory of National Security Specially Needed Medicines, Beijing, China.
  • 4. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis, NCBA), Beijing 100039, China. Electronic address: [email protected].
  • 5. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis, NCBA), Beijing 100039, China. Electronic address: [email protected].
  • 6. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis, NCBA), Beijing 100039, China. Electronic address: [email protected].
PMID: 42442359 DOI: 10.1016/j.immuni.2026.06.010
Abstract

Cytosolic DNA and RNA sensing is crucial for innate immunity, playing essential roles in pathogen defense and autoinflammation induction. We reported the Endogenous Metabolite flavin Adenine dinucleotide (FAD) as a molecular brake restraining both cytosolic DNA and RNA sensing. It bound directly to cytosolic nucleic acid sensors Cyclic GMP-AMP Synthase (cGAS) and retinoic acid-inducible gene I (RIG-I), occupying catalytic pockets to suppress their activity and downstream immune responses. Physiologically, FAD prevented self-nucleic acid-induced sterile inflammation and maintained immune homeostasis. FAD deficiency due to FAD synthase (FLAD1) ablation exacerbated auto-inflammation and Cellular Senescence. Upon Viral Infection, reduced FLAD1 activity lowered FAD amounts, which removed its inhibitory control over DNA and RNA sensors, thus facilitating extensive interferon-I (IFN-I) signaling activation. Consequently, FLAD1 depletion strengthened the innate immune response and protected mice from Viral Infection. Our findings identify FAD as a natural suppressor of both cytosolic DNA and RNA sensing, offering therapeutic potential for inflammatory diseases.

Keywords
RIG-I; autoinflammation; cGAS; cellular senescence; cytosolic DNA and RNA sensing; flavin adenine dinucleotide; immune homeostasis; type I interferon; viral infection; vitamin B2.
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