2. Academic Validation
  3. Chebulinic acid shields Villin 1 from covalent attack to mitigate Euphorbia fischeriana enterotoxicity: A basis for safer anti-ascites therapy

Chebulinic acid shields Villin 1 from covalent attack to mitigate Euphorbia fischeriana enterotoxicity: A basis for safer anti-ascites therapy

  • J Ethnopharmacol. 2025 Aug 18;353(Pt B):120435. doi: 10.1016/j.jep.2025.120435.
Hang Wang 1,  Jie Cao 2,  Sheng Li 2,  Ruolan Yang 1,  Qinman He 1,  Shengjie Hua 1,  Yuqi Pan 1,  Zeyu Jiang 1,  Xin Li 2,  Ronglu Yu 2,  Laga Litong 3,  Hongli Yu 4,  Bingbing Liu 5,  Hao Wu 6,  Xinzhi Wang 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 2 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing, Jiangsu, 210023, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 3 Affiliated Hospital of Inner Mongolia Minzu, University Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Tongliao City, Inner Mongolia, 028007, China.
  • 4 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing, Jiangsu, 210023, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. Electronic address: yhl@njucm.edu.cn.
  • 5 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing, Jiangsu, 210023, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. Electronic address: bbliu@njucm.edu.cn.
  • 6 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing, Jiangsu, 210023, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. Electronic address: whao5795@njucm.edu.cn.
  • 7 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: xinzhiwang@njucm.edu.cn.
PMID: 40835194 DOI: 10.1016/j.jep.2025.120435
Abstract

Ethnopharmacological relevance: Euphorbia fischeriana (EF), an herb used in ethnomedicine for cancerous ascites, particularly in Inner Mongolian practices, is limited by severe enterotoxicity. Traditionally, co-decoction with Terminalia chebula (TC) mitigates this toxicity, but the underlying mechanism is unknown, hindering its rational clinical development.

Aim of the study: To elucidate the molecular mechanism by which TC detoxifies EF, providing a scientific basis for developing safer EF-based therapies against malignant ascites.

Materials and methods: The study employed intestinal Organoid models, chemical biology, proteomics, and genetic engineering (Villin 1 knockout/mutagenesis). Enterotoxic EF constituents and protective TC compounds were identified, and their interactions with the cellular target Villin 1 were analyzed in vitro and validated in vivo, assessing effects on F-actin networks and intestinal barrier integrity.

Results: The EF diterpenoid Euphorin G was identified as the enterotoxin, covalently modifying Cys624 in the actin-regulatory protein Villin 1, leading to F-actin disassembly and intestinal barrier failure. Chebulinic acid from TC prevented this by non-covalently binding to Villin 1, shielding Cys624 from Euphorin G and allosterically enhancing Villin 1's F-actin binding affinity. This dual protective mechanism occurred without reducing Euphorin G levels.

Conclusions: This study reveals that Chebulinic acid from TC detoxifies EF by protecting and potentiating the host protein Villin 1 against Euphorin G. This molecular insight validates a traditional ethnopharmaceutical practice, enabling the rational development of safer EF-based therapies for refractory cancerous ascites by preserving therapeutic efficacy while mitigating toxicity.

Keywords

Chebulinic acid; Detoxification; Euphorbia fischeriana; Euphorin G; Terminalia chebula; Villin 1.

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