2. Academic Validation
  3. A loss-of-function human ADAR variant activates innate immune response and promotes bowel inflammation

A loss-of-function human ADAR variant activates innate immune response and promotes bowel inflammation

  • Nat Commun. 2025 Sep 29;16(1):8560. doi: 10.1038/s41467-025-63554-4.
Pengfei Xu # 1 2 3,  Yue Xi # 4,  Jong-Won Kim 4 5 6,  Min Zhang 4,  Chen Gao 7,  Yue Wang 4,  Meishu Xu 4,  Xingchen Wang 7,  Songrong Ren 4,  Da Yang 4,  Qingde Wang 8,  Wen Xie 9 10
Affiliations

Affiliations

  • 1 Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. pex9@pitt.edu.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China. pex9@pitt.edu.
  • 3 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China. pex9@pitt.edu.
  • 4 Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Department of Pharmacology, Institute of Medical Sciences, College of Medicine, Gyeongsang National University, Jinju, Republic of Korea.
  • 6 Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, Republic of Korea.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
  • 8 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 9 Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. wex6@pitt.edu.
  • 10 Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. wex6@pitt.edu.
  • # Contributed equally.
PMID: 41022715 DOI: 10.1038/s41467-025-63554-4
Abstract

Inflammatory bowel disease (IBD) arises from genetic-environmental interactions. Adenosine deaminases acting on RNA 1 (ADAR), an RNA-editing enzyme converting adenosine (A) to inosine (I), is essential for tissue homeostasis. Here we report that intestinal ADAR deficiency contributes to IBD pathogenesis in humans with reduced ADAR expression in patient intestinal crypts. Genetic or pharmacological inhibition of ADAR in mice causes spontaneous ileitis and colitis. Organoid studies show that ADAR loss leads to double-strand RNA (dsRNA) and endogenous retroviruses (ERVs) accumulation, disrupting intestinal homeostasis via melanoma differentiation-associated protein 5 (MDA5)-mediated dsRNA sensing and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Editome analyses identify Mda5 as an ADAR target, and edited Mda5 exhibits impaired dsRNA sensing. The human ADAR p.N173S mutation is a loss-of-function variant that fails to rescue IBD in intestinal Adar deficient mice, whereas JAK1/2 inhibitor Ruxolitinib attenuates IBD. We conclude that the ADAR-dsRNA/ERVs-MDA5-JAK/STAT axis is a potential therapeutic target for IBD.

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