Graphical Abstract. Credit: Nucleic Acids Research (2025). DOI:10.1093/nar/gkaf1511

The immune system must maintain a delicate balance to defend against harmful threats while avoiding excessive inflammation. When this balance is disrupted, immune responses can contribute to autoimmune diseases and cancer. A research team jointly led by scientists at National Taiwan University (NTU) and National Yang Ming Chiao Tung University (NYCU) has uncovered a previously unrecognized way to regulate the immune-related enzyme TREX1, offering new insight into how immune activity is controlled.

TREX1 plays a key role in processing DNA inside cells and is known to influence immune signaling pathways. Because of this central function, TREX1 has attracted attention as a potential target in cancer immunotherapy, as inhibiting TREX1 can enhance the immune visibility of cancer cells.

However, most existing approaches focus on blocking the enzyme’s active site, which can be technically challenging and may interfere with other cellular nucleases. Instead, this study explored whether TREX1 activity could be modulated through a different region that does not directly participate in its enzymatic reaction.

This project was initiated by Prof. Yu-Yuan Hsiao (NYCU), who led the initial small-molecule screening to identify a novel TREX1 inhibitor that targets a non-canonical, non-catalytic site, rather than the enzyme’s active site. Together with Prof. Jhih-Wei Chu’s team, structure-based docking and chemical analyses provided a strong foundation for subsequent biological investigation.

Building on this framework, Prof. Helene Minyi Liu’s team (NTU) carried out cell-based functional analyses to validate the biological relevance of these candidate molecules. By integrating in silico prediction with cellular validation, this work establishes a coherent pipeline from molecular design to biological function and reveals an alternative mode of TREX1 regulation. The results showed that targeting this non-catalytic region can effectively reduce TREX1 enzyme activity. The study is published in Nucleic Acids Research.

By integrating computational prediction, chemical insight, and biological validation, the study establishes a coherent pipeline that connects molecular design with biological function. Beyond its scientific findings, the work highlights the importance of interdisciplinary collaboration. By combining expertise across chemistry, structural analysis, and cell biology, the NTU and NYCU teams were able to uncover regulatory mechanisms that may have been overlooked using conventional approaches.

"By exploring non-traditional regulatory regions, we uncovered a new way to modulate an important immune-related enzyme," says co-corresponding author Prof. Minyi Liu.

Publication details

Kuan-Wei Huang et al, Disordered DNA-binding motif forms a modulation site for inhibiting the cancer immunotherapy target TREX, Nucleic Acids Research (2025). DOI: 10.1093/nar/gkaf1511 academic.oup.com/nar/article/54/2/gkaf1511/8425375

Journal information: Nucleic Acids Research

Key medical concepts

Cancer Immunotherapy

Citation: Beyond the active site: A new way to regulate immune enzyme TREX1 (2026, January 29) retrieved 29 January 2026 from https://medicalxpress.com/news/2026-01-site-immune-enzyme-trex1.html

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