2. Academic Validation
  3. Bavachinin, a main compound of Psoraleae Fructus, facilitates GSDMD-mediated pyroptosis and causes hepatotoxicity in mice

Bavachinin, a main compound of Psoraleae Fructus, facilitates GSDMD-mediated pyroptosis and causes hepatotoxicity in mice

  • Chem Biol Interact. 2024 Jul 3:111133. doi: 10.1016/j.cbi.2024.111133.
Wei Shi 1,  Yuan Gao 2,  Huijie Yang 1,  Hui Li 1,  Tingting Liu 3,  Jia Zhao 3,  Ziying Wei 3,  Li Lin 1,  Yujiao Huang 4,  Yuming Guo 3,  Anlong Xu 5,  Zhaofang Bai 6,  Xiaohe Xiao 7
Affiliations

Affiliations

  • 1 School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China; Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
  • 2 School of Traditional Chinese Medicine, Capital Medical University, Beijing, China. Electronic address: anyanggaoyuan@126.com.
  • 3 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
  • 4 School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
  • 5 School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China. Electronic address: xuanlong@bucm.edu.cn.
  • 6 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; National Key Laboratory of Kidney Diseases, China. Electronic address: baizf2008@hotmail.com.
  • 7 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; National Key Laboratory of Kidney Diseases, China. Electronic address: pharmacy_302@126.com.
PMID: 38969277 DOI: 10.1016/j.cbi.2024.111133
Abstract

Psoraleae Fructus (PF, Psoralea corylifolia L.), a traditional medicine with a long history of application, is widely used clinically for the treatment of various diseases. However, the reports of PF-related adverse reactions, such as hepatotoxicity, phototoxic dermatitis, and allergy, are increasing year by year, with liver injury being the mostly common. Our previous studies have demonstrated that PF and its preparations can cause liver injury in lipopolysaccharide (LPS)-mediated susceptibility mouse model, but the mechanism of PF-related liver injury is unclear. In this study, we showed that PF and bavachinin, a major component of PF, can directly induce the expression of Caspase-1 and interleukin-1β (IL-1β), indicating that PF and bavachinin can directly triggered the activation of inflammasome. Furthermore, pretreatment with NLR family pyrin domain-containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome inhibitors, containing MCC950, ODN TTAGGG (ODN) and carnosol, all significantly reversed bavachinin-induced inflammasome activation. Mechanistically, bavachinin dose-dependently promote Gasdermin D (GSDMD) post-shear activation and then induce mitochondrial Reactive Oxygen Species (mtROS) production and this effect is markedly inhibited by pretreatment with N-Acetylcysteine amide (NAC). In addition, combination treatment of LPS and bavachinin significantly induced liver injury in mice, but not LPS or bavachinin alone, and transcriptome analysis further validated these results. Thus, PF and bavachinin can induce the activation of inflammasome by promoting GSDMD cleavage and cause hepatotoxicity in mice. Therefore, PF, bavachinin, and PF-related preparations should be avoided in patients with inflammasome activation-associated diseases.

Keywords

Gasdermin D; Psoraleae Fructus; bavachinin; hepatotoxicity; inflammasome; mitochondrial reactive oxygen species.

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