TABLE 1.
Compounds alleviate liver fibrosis through inducing ferroptosis in HSCs.
| Drugs | Experimental model | Effects | Mode of action | Ref |
|---|---|---|---|---|
| Curcumol | HSC-T6 cells | ↑Death of activated HSCs; ↓deposition of extracellular matrix; ↑Autophagy; ↓SLC7A11 and GPX4; ↑ ACSL4 and COX2; ↑MDA; ↑ROS; ↓GSH; ↑Fe2+;↑NCOA4; ↓ FTH1 | ↑HSCs ferroptosis | Zheng et al. (2022) |
| Ellagic acid | CCl4-induced Male C57BL/6 mice | ↓ALT, AST and LDH activities; ↓ PC-III, LN, and collagen in serum; ↓degree of collagen deposition in mouse livers; ↓α-SMA, collagen type 1 (Col1a1) and TGF-β1; ↓desmin; ↓α-SMA, Col1a1 and Tgf-β1 mRNA; ↓protein levels of α-SMA and TGF-β1; ↑ FTH1 content (a main iron storage protein); impairs the formation of VAMP2/syntaxin 4 and VAMP2/synaptosome-associated protein 23 complexes by suppressing VAMP2 expression by enhancing its degradation in a proteasome-dependent pathway. This leads to the impairment of ferroportin (FPN, an iron exporter) translocation and intracellular iron extrusion | ↑HSCs ferroptosis | Li et al. (2022) |
| Ellagic acid | Bile duct ligation (BDL) mouse mode | ↓ liver fibrosis;↓ α-SMA and TGF-β1 gene expression was verified by the results of immunohistochemistry, western blot and qPCR assays | ↑HSCs ferroptosis | Li et al. (2022) |
| Ellagic acid | Bile duct ligation (BDL) mouse mode | ↓ liver fibrosis; ↓ α-SMA and TGF-β1 gene expression was verified by the results of immunohistochemistry, western blot and qPCR assays | ↑HSCs ferroptosis | Li et al. (2022) |
| Ellagic acid | TGF-β1-induced human LX-2 cells | ↑ growth inhibition; ↓ α-SMA, col1a1 and desmin expression; ↓ matrix metalloproteinase (MMP)-2 and MMP-9; ↑GSH depletion; ↑ redox-active iron accumulation; ↑ lipid peroxidation; ↓FPN | ↑HSCs ferroptosis | Li et al. (2022) |
| Ellagic acid | TGF-β1-induced primary mouse HSCs | ↑ growth inhibition; ↓ α-SMA, col1a1 and desmin expression; ↓ matrix metalloproteinase (MMP)-2 and MMP-9; ↑GSH depletion; ↑ redox-active iron accumulation; ↑ lipid peroxidation; ↓FPN | ↑HSCs ferroptosis | Li et al. (2022) |
| Ellagic acid | CCl4-induced primary mouse hepatocyte | Not suppress the growth and viability of the hepatocytes; did not trigger GSH depletion, redox-active iron overload or MDA production in primary hepatocytes or HepG2 cells | No effects | Li et al. (2022) |
| Phloridzin | CCl4-induced C57/BL6N mouse | ↓Collagen deposition and decreased levels of serum ALT, AST, laminin, and HA | NA | Shi et al. (2022) |
| Berberine | TAA and CCl4 induced mouse | ↓Liver fibrosis; ↑liver function; ↓Autophagy of HSCs; ↓HSCs activation in vivo and in vitro; ↑ROS in HSCs; ↑HSCs ferroptosis; ↑Ptgs2; ↓SLC7A11 and GPX4; ↓FTH11 and FTL; ↑p62,LC3-II,LC3-II | ↑HSCs ferroptosis | Yi et al. (2021) |
| Sorafenib | CCl4-induced C57/BL6N mouse | ↓Liver injury and ECM accumulation; ↓SLC7A11 and GPX4 of HSCs | ↑HSCs ferroptosis | Yuan et al. (2022) |
| Sorafenib | Sorafenib treated HSC-T6 cells | ↓SLC7A11, GPX4 and GSH; ↑accumulation iron, ROS and MDA; ↓HIF-1α and SLC7A11 | ↑HSCs ferroptosis | Yuan et al. (2022) |
| Wogonoside | CCl4 induced mouse | ↓Liver fibrosis (α-SMA,COL1α1); ↑SOCS1 and P53 | ↑SOCS1/P53 | Liu et al. (2022a) |
| Wogonoside | CCl4 induced HSC-T6 cells | ↓Cell viability; ↓ECM expression; ↓SLC7A11, GPX4 and GSH; ↑iron, ROS and MDA; ↑SOCS1 and P53 | ↑HSCs ferroptosis | Liu et al. (2022b) |
| Decursin | CCl4 induced C57BL/6 J mice | ↓Liver fibrosis (collagen, α-SMA, and Col1α1); ↑Fe2+, lipid ROS; ↓ GPX4 and GSH in HSCs | ↑HSCs ferroptosis | Que et al. (2022) |
| Decursin | Primary HSCs from CCl4 induced C57BL/6 J mice | ↓GPX4 and GSH; ↑ Fe2+, ROS, and Ptgs2 | ↑HSCs ferroptosis | Que et al. (2022) |
| Decursin | TGF-β-activated LX-2 cells | ↓Cell viability; ↑Ptgs2, Fe2+, ROS, and MDA; ↓ GPX4 level and GSH | ↑HSCs ferroptosis | Que et al. (2022) |
| Celastrol | CCl4 induced C57BL/6 male mice | ↓Liver injury (serum levels of AST, ALT and ALP); ↓Liver fibrosis (collagen, α-SMA, and Col1α1); ↓GPX4; ↑COX2; ↓anti-oxidant activities of PRDXs | ↑GPX4; ↓LPO | Luo et al. (2022) |
| Celastrol | LX-2 cells | ↑ Fe2+/Fe3+ and LPO; ↓ GSH; ↑ROS; ↑HO-1 | ↑HSCs ferroptosis | Luo et al. (2022) |
| Isoliquiritigenin | CCl4 induced C57BL/6 mice | ↓Liver injury (serum levels of AST and ALT); ↑DMT1 | - | Huang et al. (2022) |
| Isoliquiritigenin | HSC-T6 cells | ↑Cells viability; ↓Liver injury; ↑ROS; ↑TFR; ↑COX2; ↑DMT1; ↑POR; ↓SLC7A11; ↓GPX4; ↓DHODH | ↑HSCs ferroptosis | Huang et al. (2022) |
| Isoliquiritigenin | TAA induced zebrafish | ↓Liver fibrosis (collagen, α-SMA, and Col1α1); ↑iron; ↑ROS | - | Huang et al. (2022) |
| DHA | CCl4 induced SD rat | ↓Liver injury (serum ALT, AST, ALP, LDH and TBIL); ↓Liver fibrosis (α-SMA, collagen I, fibronectin); ↓collagen deposition | ↑HSCs ferroptosis | Zhang et al. (2021) |
| DHA | PDGF-BB-induced primary HSCs | ↓Cells viability; ↓Liver fibrosis; ↓α-SMA, collagen I, fibronectin and MMP13 (protein and mRNA); ↓collagen deposition; ↓TGF-βR and PDGF-Rβ mRNA; ↑ACSL4; ↓SLC7A11; ↑ Fe2+, ROS, and MDA; ↓ GPX4 and GSH; ↑NCOA4 | ↑HSCs ferroptosis | Zhang et al. (2021) |
| MgIG | CCl4 induced SD rat | ↓Liver injury (serum ALT, AST, ALP, LDH and TBIL); ↓serum HA, LN, PC-III and IV-C levels; ↓Liver fibrosis (α-SMA, collagen I, fibronectin and demin); ↓TGF-βR1 and PDGF-βR | - | Sui et al. (2018) |
| MgIG | HSC-T6 cells | ↓α-SMA, collagen1, demin and fibronectin; ↓TGF-βR1,PDGF-βR and EGFR; ↓TIMP1 and TIMP2; ↑MMP2 and MMP9; ↑ Fe2+, ROS, 4-HNE and MDA; ↑TF,TfR,FTH1, HO-1; ↓FPN | ↑HSCs ferroptosis | Sui et al. (2018) |
| Artesunate | Primary HSCs isolated from CCl4 induced mice | ↓Cell vitality; ↑cell death rate; ↑iron; ↑lipid peroxides and reduced antioxidant capacity; ↑LC3,Atg3, Atg5, Atg6/beclin1, Atg12; ↓p62, FTH1, NCOA4; ↑ferritinophagy | ↑HSCs ferroptosis | Kong et al. (2019) |
| Artesunate | CCl4 induced mice | ↑HSCs ferroptosis; ↓Liver fibrosis including HA, LN, PC-III, and IVeC; ↑Fe2+, lipid ROS, Ptgs2 mRNA; ↓GSH | ↑HSCs ferroptosis | Kong et al. (2019) |
| Artemether | CCl4 induced mice | ↓Liver fibrosis; ↓α-SMA, collagen I, fibronectin (protein and mRNA); ↓Liver injury (ALT, AST and ALP levels in liver and serum); ↓serum HA, LN, PC-III and IV-C levels; ↓ECM deposition (massive collagen); ↓hydroxyproline in liver and serum; ↓PDGF-βR and EGFR | ↑HSCs ferroptosis | Wang et al. (2019) |
| Artemether | HSC-T6 cells | ↓HSCs activation (↓α-SMA, α1(I)collagen, and fibronectin); ↑ Fe2+ and LPO; ↓TGF-βR1, PDGF-βR, and EGFR (IF); α-SMA, α1(I)collagen, fibronectin, TGF-βR1, PDGF-βR, and EGFR (WB); α-SMA, α1(I) collagen and fibronectin (RT-PCR) | ↑HSCs ferroptosis | Wang et al. (2019) |
| WBME | LPS-induced HSCs-T6 cells | ↑Cell death rate; ↑ROS; ↑ lipid ROS; ↓CTGF,α-SMA,integrin-β1 and p-JNK; ↓ GPX4 and SLC7A11; ↑CHOP | ↑HSCs ferroptosis | Ho et al. (2021) |
| Chrysophanol | Rat HSC-T6 cells expressing HBx | ↓Cell vitality; ↑ lipid ROS; ↑ER stress; ↓CTGF,α-SMA; ↓ GPX4 and SLC7A11 | ↑HSCs ferroptosis | Kuo et al. (2020) |
| DHA | HSC-LX2 and Primary | ↓HSCs activation; ↓α-SMA, fibronectin and collagen I; ↑ Fe2+;↑ ROS; ↑ MDA;↓ GSH; ↑ autophagy; ↑ FTO-mediated m6A methylation of BECN1 | ↑HSCs ferroptosis | Shen et al. (2022) |
| DHA | CCl4 induced mice | ↓Liver injury; ↓Liver fibrosis; ↓α-SMA (ICH); ↓ACTA2, collagen I and demin (mRNA) | ↑HSCs ferroptosis | Shen et al. (2022) |
↑,promote, upregulate or increase; ↓,inhibit, downregulate or decrease; α-SMA, α-smooth muscle actin; ACSL4, acyl-coA synthetase long-chain family member four; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; Atg, autophagy related genes; CHOP, CCAAT enhancer-binding protein homologous protein; CCl4, carbon tetrachloride; COL1α1,α1(I)collagen; CTGF, connective tissue growth factor; DHA, dihydroartemisinin; ECM, extracellular matrix; FGF21, Fibroblast growth factor 21; GPX4, glutathione peroxidase 4; GSH, glutathione; HA, hyaluronic acid; HSCs, hepatic stellate cell; HYP, hydroxyproline; IV C, collagen type IV; LC3, microtubule-associated protein light chain 3; PDGF-BB, Platelet-derived growth factor BB; FPN, ferroportin; FTH1, ferritin heavy chain 1; LDH, lactate dehydrogenase; LPS, lipopolysaccharid; MDA, malondialdehyde; MgIG, magnesium isoglycyrrhizinate; MMP13, matrix metalloprotease 13; NCOA4, nuclear receptor co-activator 4; PC-III, procollagen type III; PDGF, platelet-derived growth factor; PDGF-BB, platelet-derived growth factor BB; Ptgs2,Prostaglandin endoperoxide synthase 2; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; TBIL, total bilirubin; TF, transferrin; TGFβ, transforming growth factor β; TfR, transferrin receptor; TAA, thioacetamide; WBME, Wild Bitter Melon Extract; VAMP2,vesicle-associated membrane protein 2.