Decursin ameliorates carbon-tetrachloride-induced liver fibrosis by facilitating ferroptosis of hepatic stellate cells

Abstract

Decursin possesses the potential to alleviate transforming growth factor (TGF)-β-induced hepatic stellate cells (HSCs) activation. However, the mechanisms by which decursin alleviates hepatic fibrosis remain not fully understood. Our aim is to explore the function of decursin on regulating HSCs activation and hepatic fibrosis. The anti-fibrotic effect of decursin was evaluated by Masson and Sirius red staining, and immunohistochemical (IHC) and quantitative real-time PCR (qRT-PCR) analysis for alpha-smooth muscle actin (α-SMA) and collagen types I (Col1a1) expression. Ferroptosis was assessed by measuring iron concentration, glutathione peroxidase 4 (Gpx4) and Prostaglandin endoperoxide synthase 2 (Ptgs2) expression, glutathione (GSH) level, lipid peroxidation, and reactive oxygen species (ROS) level. We found that decursin treatment decreased CCl4-induced liver fibrosis. The primary HSCs isolated from decursin-treated group showed an increased Fe2+, lipid ROS level, and decreased Gpx4 and GSH levels compared with HSCs from model group. Moreover, decursin promoted ferroptosis in activated HSCs in vitro, as evidenced by declined Gpx4 and GSH levels, increased Fe2+, ROS, and Ptgs2 levels compared with control. More important, ferroptosis inhibitor destroyed the anti-fibrosis effect of decursin on HSCs. In summary, these data suggest that decursin has potential to treat hepatic fibrosis.

Hepatoprotective Mechanism of Apigenin via Suppression of Oxidative Inflammatory Signaling and Apoptosis against Hepatotoxicity Induced by CCl4 in Rats

“…It is an exogenous industrial solvent with a strong affinity for the liver and it has been recognized as a hepatotoxicant (Zhou et al, 2020). In spite of its hepatotoxic and nephrotoxic stress in humans and experimental animals, it is still being used in dry cleaning, fumigation of grains, insecticide and filling fire extinguishers (Que et al, 2022). The hepatic metabolism of CCl 4 via the action of cytochrome P450-dependent monooxygenases results in the production of its hepatic metabolites, trichloromethyl (CCl 3 ) and trichloromethyl peroxyl ( • OOCCl 3 ) reactive oxygen species (ROS) El- (Hadary and Hassanien, 2016).…”

Pharmacological modulation of ferroptosis as a therapeutic target for liver fibrosis

“…Mounting evidence from in vitro and in vivo models indicates that pharmacological induction of ferroptosis may mitigate liver fibrosis development ( Table 1 ). Moreover, there is an increasing body of evidence showing that inducing HSCs ferroptosis using Curcumol ( Zheng et al, 2022 ), ellagic acid ( Li et al, 2022 ), phloridzin ( Shi et al, 2022 ), liraglutide ( Song et al, 2022 ), berberine ( Yi et al, 2021 ), wogonoside ( Liu et al, 2022 ), decursin ( Que et al, 2022 ), celastrol ( Luo et al, 2022 ),isoliquiritigenin ( Huang et al, 2022 ), DHA ( Zhang et al, 2021 ; Shen et al, 2022 ), wild bitter melon extract (WBME) ( Ho et al, 2021 ),chrysophanol ( Kuo et al, 2020 ), magnesium isoglycyrrhizinate ( Sui et al, 2018 ), artesunate ( Kong et al, 2019 ), and artemether ( Wang et al, 2019 ) has potential as a therapeutic strategy to prevent or inhibit liver fibrosis. Curcumol ( Zheng et al, 2022 ), ellagic acid ( Li et al, 2022 ), wogonoside ( Liu et al, 2022 ), decursin, sorafenib, berberine, celastrol ( Luo et al, 2022 ), isoliquiritigenin ( Huang et al, 2022 ), DHA ( Zhang et al, 2021 ), WBME ( Ho et al, 2021 ), and chrysophanol ( Kuo et al, 2020 ) alleviate liver fibrosis through inducing ferroptosis by inhibiting SLC7A11.…”

Ferroptosis as an emerging therapeutic target in liver diseases

“…Recently, Hang et al reported that ISL alleviated liver fibrosis by triggering HSCs ferroptosis through the suppression of GPX4 and elevation of TfR and DMT1 expression, thereby generating a significant amount of ROS ( Huang et al, 2022b ). Another study showed that decursin administration reduced CCl4-induced hepatic fibrosis by raising Fe2+ and lipid ROS levels and decreasing GSH and GPX4 levels ( Que et al, 2022 ). Furthermore, Kuo et al (2020) discovered that chrysophanol from the rhizomes of Rheum palmatum L. could reduce ER stress and promote ferroptosis, which in turn mediates the activation of HSC-T6 and alleviates HBV X protein-induced liver fibrosis.…”