Berberine alleviates liver fibrosis through inducing ferrous redox to activate ROS-mediated hepatic stellate cells ferroptosis

Abstract

Berberine (BBR) has been explored as a potential anti-liver fibrosis agent, but the underlying mechanisms are unknown. In the current study, we aimed to investigate the molecular mechanisms underlying the effect of BBR against liver fibrogenesis in thioacetamide (TAA) and carbon tetrachloride (CCl4) induced mouse liver fibrosis. In addition to i.p. injection with TAA or CCl4, mice in the treatment group received BBR intragastrically. Concurrently, combined with TAA and BBR treatment, mice in the inhibitor group were injected i.p. with ferrostatin-1 (Fer-1). Hepatic stellate cells (HSCs) were also used in the study. Our results showed that BBR obviously alleviated mouse liver fibrosis and restored mouse liver function; however, the pharmacological effects of BBR against liver fibrosis were significantly diminished by Fer-1 treatment. Mechanically, BBR impaired the autophagy–lysosome pathway (ALP) and increased cell reactive oxygen species (ROS) production in HSCs. ROS accelerated the breakdown of the iron-storage protein ferritin and sped up iron release from ferritin, which resulted in redox-active iron accumulation in HSCs. Lipid peroxidation and glutathione (GSH) depletion triggered by the Fenton reaction promoted ferroptosis and attenuated liver fibrosis. Furthermore, impaired autophagy enhanced BBR-mediated ferritin proteolysis to increase cellular ferrous overload via the ubiquitin–proteasome pathway (UPS) in HSCs and triggered HSC ferroptosis. Collectively, BBR alleviated liver fibrosis by inducing ferrous redox to activate ROS-mediated HSC ferroptosis. Our findings may be exploited clinically to provide a potential novel therapeutic strategy for liver fibrosis.

Therapeutic Effects of Berberine on Liver Fibrosis are associated With Lipid Metabolism and Intestinal Flora

“…Abnormal endoplasmic reticulum (ER) stress, oxidative stress, autophagy and ferroptosis, accompanied by inflammasome-associated signals, are common features of fibrogenesis. ( Koo et al, 2016 ; Kim et al, 2017 ; Yang et al, 2021 ; Yi et al, 2021 ; Zhang et al, 2021 ). However, the pathogenesis of HSC activation and liver fibrosis remains unclear.…”

“…In fibrotic mouse models, we found that BBR alleviates liver fibrosis by inducing ferrous-ion redox reactions to activate reactive oxygen species (ROS)-mediated ferroptosis in hepatic stellate cells, which suggests a possible strategy for the treatment of liver fibrosis. ( Yi et al, 2021 ). Similar effects of BBR in carbon tetrachloride (CCl 4 )-induced liver fibrosis models were also demonstrated by other team recently.…”

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

“…In addition, damaged autophagy potentiated BBRmediated ferritin hydrolysis, which increased cellular iron overload and triggered HSC iron death through the ubiquitin-proteasome pathway in HSC. Overall, BBR reduces LF through triggering ferrous redox to activate iron death in HSCs [218] .…”

The Regulatory Roles of Polysaccharides and Ferroptosis-Related Phytochemicals in Liver Diseases

“…For one thing, phytochemicals could induce ferroptosis to suppress the progression of liver fibrosis and HCC. For instance, magnesium isoglycyrrhizinate, derivatives of artemisinin (such as artemether, artesunate, and dihydro-artemisinin (DHA)), wild bitter melon extracts, chrysophanol, and zalkaloid berberine could block the development of liver fibrosis by triggering HSC ferroptosis [ 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 ]. Besides, several studies revealed that DHA could trigger ferroptosis to block HCC growth by promoting PEBP1/15LO formation or an unfolded protein response [ 153 , 154 ].…”