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A derivative of tanshinone IIA and salviadione, 15a, inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2

Acta Pharmacologica Sinica volume 46, pages 672–686 (2025)Cite this article

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg−1·d−1) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg−1·d−1, i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 μM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

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Fig. 1: Compound 15a attenuates colonic damage in the DSS-induced acute colitis mouse model.
Fig. 2: Compound 15a reduces inflammatory response in the DSS-induced acute colitis mouse model.
Fig. 3: Compound 15a attenuates colonic damage in the DSS-induced chronic colitis mouse model.
Fig. 4: Compound 15a reduces inflammatory response in the DSS-induced chronic colitis mouse model.
Fig. 5: Identification of RIPK2 as the direct binding target of compound 15a.
Fig. 6: Compound 15a alleviates both acute and chronic colitis by inhibiting the activation of RIPK2.
Fig. 7: Compound 15a suppresses the NF-κB and MAPK signaling pathways by inhibiting the activation of RIPK2 in intestinal epithelial cells.

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Acknowledgements

This study was supported by the Key Scientific Research Project of Wenzhou City (ZY2021021 to YW) and the National Natural Science Foundation of China (82361138563 to YW).

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Authors and Affiliations

  1. School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China

    Cheng-hong Hu, Zhe Wang, Wei-yang Tang, Lei-yu Xu, Fang-min Ning, Xiao-hong Wei & Yi Wang

  2. Chemical Biology Research Center, Wenzhou Medical University, School of Pharmaceutical Sciences, Wenzhou, 325035, China

    Yue Chen, Tian-yang Jin, Bo Jin, Jing Liao & Ling-xi Zhang

  3. Pharm-X Center, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China

    Chun-yong Ding & Ao Zhang

  4. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310051, China

    Guang Liang

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Contributions

YW, XHW, GL and CHH contributed to the literature search and study design. YW, XHW and CHH participated in the drafting of the article. CHH, YC, TYJ, ZW, BJ, JL, CYD, AZ, WYT, LXZ, LYX and FMN carried out the experiments. YW, XHW, GL and CHH revised the manuscript. YW, XHW, GL and CHH contributed to data collection and analysis.

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Correspondence to Xiao-hong Wei or Yi Wang.

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Hu, Ch., Chen, Y., Jin, Ty. et al. A derivative of tanshinone IIA and salviadione, 15a, inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2. Acta Pharmacol Sin 46, 672–686 (2025). https://doi.org/10.1038/s41401-024-01399-1

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