Therapeutic targeting of the tryptophan-kynurenine-aryl hydrocarbon receptor pathway with apigenin in MED12-mutant leiomyoma cells

Approximately 77.4% of uterine leiomyomas carry MED12 gene mutations (mut-MED12), which are specifically associated with strikingly upregulated expression and activity of the tryptophan 2,3-dioxygenase (TDO2) enzyme, leading to increased conversion of tryptophan to kynureine. Kynurenine increases leiomyoma cell survival by activating the aryl hydrocarbon receptor (AHR). We used a leiomyoma-relevant model, in which a MED12 Gly44 mutation was knocked in by CRISPR in a human uterine myometrial smooth muscle (UtSM) cell line, in addition to primary leiomyoma cells from 26 patients to ascertain the mechanisms responsible for therapeutic effects of apigenin, a natural compound. Apigenin treatment significantly decreased cell viability, inhibited cell cycle progression, and induced apoptosis preferentially in mut-MED12 versus wild-type primary leiomyoma and UtSM cells. Apigenin not only blocked AHR action but also decreased TDO2 expression and kynurenine production, preferentially in mut-MED12 cells. Apigenin did not alter TDO2 enzyme activity. TNF and IL-1β, cytokines upregulated in leiomyoma, strikingly induced TDO2 expression levels via activating the NF-κB and JNK pathways, which were abolished by apigenin. Apigenin or a TDO2 inhibitor decreased UtSM cell viability induced by TNF/IL-1β. We provide proof-of-principle evidence that apigenin is a potential therapeutic agent for mut-MED12 leiomyomas. This is a preview of subscription content, access via your institution Access options Subscribe to this journal Receive 12 print issues and online access 251,40 € per year only 20,95 € per issue Buy this article - Purchase on SpringerLink - Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout Similar content being viewed by others Data availability The study data are included in the manuscript and/or in the supplemental information.

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This study was supported by NIH grants P50HD098580 and R01ES034753 (to SEB and PY), and Northwestern Memorial Foundation (to PY) and (to MA). The Northwestern University core facilities of Flow Cytometry, Sanger Sequencing, and Metabolomics are co-funded by National Cancer Institute Cancer Center Grant CA060553. Author information Authors and Affiliations Contributions Author contributions: TI, PY, and SEB designed the research; TI, AZ, HW, JSC, MLA, and SK performed the research; TI, PY, MA, KB, and SEB analyzed the data; and TI, PY, and SEB wrote the paper. All authors approved the final manuscript for submission. Corresponding author Ethics declarations Competing interests The authors declare no competing interests. Ethics approval All methods were performed in accordance with the relevant guidelines and regulations. The institutional review board at Northwestern University approved this study. Informed consent was obtained before surgery. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Iizuka, T., Zuberi, A., Wei, H. et al. Therapeutic targeting of the tryptophan-kynurenine-aryl hydrocarbon receptor pathway with apigenin in MED12-mutant leiomyoma cells. Cancer Gene Ther 32, 393–402 (2025). https://doi.org/10.1038/s41417-025-00881-0 Received: Revised: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1038/s41417-025-00881-0 This article is cited by - The aryl hydrocarbon receptor: structure, signaling, physiology and pathology Signal Transduction and Targeted Therapy (2026)