Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratic hepatotoxicity

Abstract

Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.

Keywords

Psoraleae Fructus / bavachin / idiosyncratic drug-induced liver injury / caspase-1 / IL-1β / NLRP3 inflammasome

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Acknowledgements

This work has been supported by the Beijing Nova Program (No. Z181100006218001), the National Natural Science Foundation of China (Nos. 81874368, 81630100, 81903891, and 81573676), the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” (Nos. 2017ZX09301022 and 2018ZX09101002-001-002), and the Innovation Groups of the National Natural Science Foundation of China (No. 81721002).

Compliance with ethics guidelines

Nan Qin, Guang Xu, Yan Wang, Xiaoyan Zhan, Yuan Gao, Zhilei Wang, Shubin Fu, Wei Shi, Xiaorong Hou, Chunyu Wang, Ruisheng Li, Yan Liu, Jiabo Wang, Haiping Zhao, Xiaohe Xiao, and Zhaofang Bai declare that they have no conflict of interest. This study was ratified by the Experimental Animal Center of the Fifth Medical Centre, Chinese PLA General Hospital in Beijing, China. Approval for the animal experimental research was in accordance with the ethical standards of the Ethics Committee in the Fifth Medical Centre, Chinese PLA General Hospital.

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