Discovery of a novel AhR–CYP1A1 axis activator for mitigating inflammatory diseases using an in situ functional imaging assay

Zhang, Feng, Zhao, Bei, Fan, Yufan, Qin, Lanhui, Shi, Jinhui, Chen, Lin, Xu, Leizhi, Jin, Xudong, Sun, Mengru, Deng, Hongping, Zeng, Hairong, Xiao, Zhangping, Yang, Xin ORCID: https://orcid.org/0000-0002-8429-7598 and Ge, Guangbo 2025. Discovery of a novel AhR–CYP1A1 axis activator for mitigating inflammatory diseases using an in situ functional imaging assay. Acta Pharmaceutica Sinica B 15 (1) , pp. 508-525. 10.1016/j.apsb.2024.09.014

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Abstract

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR–CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR–CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR–CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR–CYP1A1 axis as novel anti-inflammatory agents.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Engineering
Publisher:	Elsevier
ISSN:	2211-3835
Funders:	National Natural Science Foundation of China, National Key Research and Development Program of China, Shanghai Science and Technology Innovation Action Plans, Shanghai University of Traditional Chinese Medicine, Shanghai Municipal Health Commission, National Administration of Traditional Chinese Medicine, State Key Laboratory of Fine Chemicals
Date of First Compliant Deposit:	31 October 2024
Date of Acceptance:	13 September 2024
Last Modified:	04 Mar 2025 12:37
URI:	https://orca.cardiff.ac.uk/id/eprint/173389

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