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Peer-reviewedCC BY-NC 4.0Cancer Biology & Therapy

The Zα domain of ADAR1: emerging roles in cancer biology and evidence as a promising therapeutic target

  • Jie Ying Teo1,2
  • Pei San Yee1
  • Sarah Azrai2
  • Stephanie Hao Ling Cheah1,3
  • Siew Kit Ng2
  • Keng Yoon Yeong4
  • Xavier Wezen Chee3,5
  • Siaw San Hwang3
  • Sok Ching Cheong1,6,7
  • Annie Wai Yeeng Chai1
7 affiliations
  1. 1Translational Cancer Biology, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  2. 2Department of Biomedical Science, Pusat Kanser Tun Abdullah Ahmad Badawi, Universiti Sains Malaysia, Pulau Pinang, Malaysia
  3. 3School of Research, Faculty of Chemical Engineering and Science, Swinburne University of Technology Sarawak Campus, Kuching, Sarawak, Malaysia
  4. 4School of Science, Monash University Malaysia, Subang Jaya, Selangor, Malaysia
  5. 5Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  6. 6Department of Oral & Maxillofacial Clinical Sciences, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur, Malaysia
  7. 7Oral Cancer Research and Coordinating Centre (OCRCC), Faculty of Dentistry, Universiti Malaya, Kuala Lumpur, Malaysia
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Abstract

Adenosine deaminase acting on RNA 1 (ADAR1) has emerged as an important cancer dependency and suppressor of innate immunity. While early therapeutic strategies focused on global enzymatic inhibition, these approaches may compromise essential homeostatic functions of the constitutively expressed ADAR1-p110 isoform. Growing evidence highlights editing-independent functions uniquely mediated by the interferon-inducible ADAR1-p150 isoform. Through its conformation-specific Zα domain, ADAR1-p150 binds Z-nucleic acids and suppresses MDA5-, PKR-, and ZBP1-driven innate immune activation, thereby promoting tumor immune evasion and adaptation to inflammatory stress. Consequently, selectively disrupting this p150-mediated suppression may represent a more therapeutically tractable strategy than global ADAR1 inhibition, with the Zα domain providing a potentially selective mechanistic interface. This review synthesizes current understanding of Zα-mediated immune regulation, evaluates emerging domain-specific therapeutic approaches, and provides a comprehensive guide to the biophysical and cell-based assays used to interrogate Zα interactions, highlighting key mechanistic gaps that may inform future p150-selective translational interventions.

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Cite

BibTeXRIS
BibTeX
@article{teo2026domain,
  title = {{The Zα domain of ADAR1: emerging roles in cancer biology and evidence as a promising therapeutic target}},
  author = {Jie Ying Teo and Pei San Yee and Sarah Azrai and Stephanie Hao Ling Cheah and Siew Kit Ng and Keng Yoon Yeong and Xavier Wezen Chee and Siaw San Hwang and Sok Ching Cheong and Annie Wai Yeeng Chai},
  journal = {Cancer Biology \& Therapy},
  year = {2026},
  month = oct,
  doi = {10.1080/15384047.2026.2749935},
  url = {https://doi.org/10.1080/15384047.2026.2749935},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - The Zα domain of ADAR1: emerging roles in cancer biology and evidence as a promising therapeutic target
AU  - Jie Ying Teo
AU  - Pei San Yee
AU  - Sarah Azrai
AU  - Stephanie Hao Ling Cheah
AU  - Siew Kit Ng
AU  - Keng Yoon Yeong
AU  - Xavier Wezen Chee
AU  - Siaw San Hwang
AU  - Sok Ching Cheong
AU  - Annie Wai Yeeng Chai
PY  - 2026
DA  - 2026/10/30
JO  - Cancer Biology & Therapy
DO  - 10.1080/15384047.2026.2749935
UR  - https://doi.org/10.1080/15384047.2026.2749935
AB  - Adenosine deaminase acting on RNA 1 (ADAR1) has emerged as an important cancer dependency and suppressor of innate immunity. While early therapeutic strategies focused on global enzymatic inhibition, these approaches may compromise essential homeostatic functions of the constitutively expressed ADAR1-p110 isoform. Growing evidence highlights editing-independent functions uniquely mediated by the interferon-inducible ADAR1-p150 isoform. Through its conformation-specific Zα domain, ADAR1-p150 binds Z-nucleic acids and suppresses MDA5-, PKR-, and ZBP1-driven innate immune activation, thereby promoting tumor immune evasion and adaptation to inflammatory stress. Consequently, selectively disrupting this p150-mediated suppression may represent a more therapeutically tractable strategy than global ADAR1 inhibition, with the Zα domain providing a potentially selective mechanistic interface. This review synthesizes current understanding of Zα-mediated immune regulation, evaluates emerging domain-specific therapeutic approaches, and provides a comprehensive guide to the biophysical and cell-based assays used to interrogate Zα interactions, highlighting key mechanistic gaps that may inform future p150-selective translational interventions.
SN  - 1538-4047
SN  - 1555-8576
ER  -