Wild Bitter Melon Extract Regulates LPS-Induced Hepatic Stellate Cell Activation, Inflammation, Endoplasmic Reticulum Stress, and Ferroptosis

Chang-Hsun Ho; Jen-Hsuan Huang; Maw-Sheng Sun; I-Shiang Tzeng; Yi-Chiung Hsu; Chan-Yen Kuo

doi:10.1155/2021/6671129

Wild Bitter Melon Extract Regulates LPS-Induced Hepatic Stellate Cell Activation, Inflammation, Endoplasmic Reticulum Stress, and Ferroptosis

Evid Based Complement Alternat Med. 2021 Jun 22:2021:6671129. doi: 10.1155/2021/6671129. eCollection 2021.

Authors

Chang-Hsun Ho¹, Jen-Hsuan Huang¹, Maw-Sheng Sun^{1

2}, I-Shiang Tzeng³, Yi-Chiung Hsu⁴, Chan-Yen Kuo³

Affiliations

¹ Department of Anesthesiology, Show Chwan Memorial Hospital, Changhua, Taiwan.
² Department of Nursing, Meiho University, Pingtung, Taiwan.
³ Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan.
⁴ Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan.

Abstract

The activation of hepatic stellate cells (HSCs) is a key component of liver fibrosis. Two antifibrosis pathways have been identified, the reversion to quiescent-type HSCs and the clearance of HSCs through apoptosis. Lipopolysaccharide- (LPS-) induced HSCs activation and proliferation have been associated with the development of liver fibrosis. We determined the pharmacological effects of wild bitter melon (WM) on HSC activation following LPS treatment and investigated whether WM treatment affected cell death pathways under LPS-treated conditions, including ferroptosis. WM treatment caused cell death, both with and without LPS treatment. WM treatment caused reactive oxygen species (ROS) accumulation without LPS treatment and reversed the decrease in lipid ROS production in HSCs after LPS treatment. We examined the effects of WM treatment on fibrosis, endoplasmic reticulum (ER) stress, inflammation, and ferroptosis in LPS-activated HSCs. The western blotting analysis revealed that the WM treatment of LPS-activated HSCs induced the downregulation of the connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), integrin-β1, phospho-JNK (p-JNK), glutathione peroxidase 4 (GPX4), and cystine/glutamate transporter (SLC7A11) and the upregulation of CCAAT enhancer-binding protein homologous protein (CHOP). These results support WM as an antifibrotic agent that may represent a potential therapeutic solution for the management of liver fibrosis.