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Direct inhibition of the TXNIP-NLRP3-GSDMD pathway reduces pyroptosis in colonocytes and alleviates ulcerative colitis in mice by the small compound PEITC

Acta Pharmacologica Sinica volume 46, pages 2436–2449 (2025)Cite this article

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The etiology of UC is multifaceted, and the underlying pathogenesis remains incompletely understood. Pyroptosis, programmed cell death mediated by the gasdermins, is a pivotal driver of UC pathology due to its dual role in epithelial barrier disruption and inflammatory amplification. We previously showed that phenethyl isothiocyanate (PEITC), an isothiocyanate derived from cruciferous vegetables, alleviated acute liver injury in mice by suppressing hepatocyte pyroptosis. In this study we evaluated the therapeutic potential of PEITC in the treatment of UC and the underlying mechanisms. UC mouse models were established by administration of 2.5% (w/v) dextran sulfate sodium (DSS) daily for 7 days. PEITC (5, 10, or 20 mg·kg−1·d−1, i.g.) was given 2 days before the start of modeling, and the dosing lasted for a total of 10 days. We showed that during the progression of DSS-induced UC, the pyroptosis pathway was activated accompanied by elevated expression levels of thioredoxin-interacting protein (TXNIP) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), as well as the activation of caspase-1, gasdermin D (GSDMD) and interleukin-1β (IL-1β). Treatment with PEITC dose-dependently reduced TXNIP and NLRP3 expression while inhibiting the cleavage of proteins associated with the pyroptosis pathway such as caspase-1, GSDMD, and IL-1β. We confirmed the inhibitory effect of PEITC on colonocyte pyroptosis in an in vitro model established in HT29 cells, where PEITC (0.2, 1, 5 µM) dose-dependently inhibited TXNIP and NLRP3 expression and the activation of pro-caspase-1, GSDMD and pro-IL-1β. We revealed that PEITC is directly bound to TXNIP and disrupted the interaction between TXNIP and NLRP3, leading to diminished cellular inflammation and oxidative stress levels. In conclusion, this study demonstrates that PEITC disrupts the interaction of TXNIP and NLRP3 by binding to TXNIP, inhibits NLRP3 activation and colonocyte pyroptosis, and thus effectively alleviates UC symptoms in mice. This study offers novel drug targets along with potential therapeutic candidates for the clinical prevention and treatment of UC.

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Fig. 1: UC mice presented elevated levels of intestinal inflammation and oxidative stress.
Fig. 2: Pyroptosis signaling was activated in the colon tissue of DSS-induced UC model mice.
Fig. 3: PEITC dose-dependently alleviated UC in mice.
Fig. 4: PEITC inhibited the activation of pyroptosis signaling in the colon tissue of UC mice.
Fig. 5: PEITC inhibited pyroptosis in HT29 cells in vitro.
Fig. 6: PEITC bound to TXNIP and attenuated its binding to NLRP3.
Fig. 7: TXNIP knockdown downregulated pyroptosis signaling.
Fig. 8: Schematic diagram of the molecular mechanism by which PEITC inhibits intestinal epithelial cell pyroptosis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82073910, 82473989, 82230116).

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  1. These authors contributed equally: Jie Wang, Cui Zhang.

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, 210000, China

    Jie Wang, Cui Zhang, Jia Qin, Ning An, Mei Bai, Rong-hui Du, Yan Shen, Xu-dong Wu, Xue-feng Wu & Qiang Xu

  2. School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 210000, China

    Jie Wang

  3. Drug R&D Institute, JC (Wuxi) Company, Inc., Wuxi, 214000, China

    Jing-cai Cheng

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Contributions

JW, XFW, and QX designed research. JW, CZ, JQ, NA, and MB performed research and analyzed data. RHD, YS, XDW, JCC, XFW, and QX contributed new reagents. JW and XFW wrote the paper. All of the authors have approved the final manuscript.

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Correspondence to Xue-feng Wu or Qiang Xu.

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Jing-cai Cheng is the employee of Drug R&D Institute, JC (Wuxi) Company, Inc. He declares no competing interests.

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Wang, J., Zhang, C., Qin, J. et al. Direct inhibition of the TXNIP-NLRP3-GSDMD pathway reduces pyroptosis in colonocytes and alleviates ulcerative colitis in mice by the small compound PEITC. Acta Pharmacol Sin 46, 2436–2449 (2025). https://doi.org/10.1038/s41401-025-01549-z

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