Xiao-Yao-San protects against anti-tuberculosis drug-induced liver injury by regulating Grsf1 in the mitochondrial oxidative stress pathway

Zijun Bai; Weiwei Tao; Yiqun Zhou; Yi Cao; Shun Yu; Zheng Shi

doi:10.3389/fphar.2022.948128

Xiao-Yao-San protects against anti-tuberculosis drug-induced liver injury by regulating Grsf1 in the mitochondrial oxidative stress pathway

Front Pharmacol. 2022 Sep 1:13:948128. doi: 10.3389/fphar.2022.948128. eCollection 2022.

Authors

Zijun Bai^{1

2}, Weiwei Tao¹, Yiqun Zhou³, Yi Cao⁴, Shun Yu⁴, Zheng Shi⁴

Affiliations

¹ School of Chinese Medicine, School of Integrated Chinese and Western Medicine Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
² Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China.
³ Department of Infectious Disease, Suzhou Integrated Chinese and Western Medicine Hospital, Suzhou, Jiangsu, China.
⁴ Institute of Literature in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

Abstract

Background: Xiao-Yao-San (XYS) is a traditional Chinese prescription that regulates gastrointestinal function, improves mental and psychological abnormalities, and enhances liver function. However, the underlying mechanism of XYS for relieving anti-tuberculosis (AT) drug-induced liver injury is not clear. Objective: The current study examined whether XYS alleviated the symptoms of AT drug-induced liver injury in mice via the mitochondrial oxidative stress pathway. Methods: BALB/c male mice were randomly divided into four groups of 12 animals, including a control group, a model group, a 0.32 g/kg XYS group, and a 0.64 g/kg XYS group. The effect of XYS on the degree of liver injury was observed using haematoxylin and eosin staining (HE) and oil red O staining of pathological sections, biochemical parameters, and reactive oxygen species (ROS) levels. The protein expression of mitochondrial synthesis-related proteins and ferroptosis-related proteins was examined using Western blotting. Results: XYS improved the pathological changes in liver tissue and reduced the level of oxidative stress in liver-injured mice. XYS increased the expression of mitochondrial synthesis-related proteins and reversed the expression of ferroptosis-related proteins. Knockdown of G-rich RNA sequence binding factor 1 (Grsf1) expression with Grsf1 shRNA blocked the protective effects of XYS in liver injury. Conclusion: Our findings suggest that XYS alleviates AT drug-induced liver injury by mediating Grsf1 in the mitochondrial oxidative stress pathway.

Keywords: DILI; Grsf1 shRNA; RUCAM; Xiao-Yao-San; anti-tuberculosis drugs; ferroptosis; mitochondria synthesis.