Journal of ethnopharmacology · 2025
Chebulinic acid shields Villin 1 from covalent attack to mitigate Euphorbia fischeriana enterotoxicity: A basis for safer anti-ascites therapy.
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Wang Hang, Cao Jie, Li Sheng, Yang Ruolan, He Qinman, Hua Shengjie, Pan Yuqi, Jiang Zeyu, Li Xin, Yu Ronglu, Litong Laga, Yu Hongli, Liu Bingbing, Wu Hao, Wang Xinzhi
Аннотация
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.
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.