Table 2.

Preclinical research cholestatic liver diseases

Area of concern	Findings	Approach	Ref.
Mitochondrial damage by GCDCA	Mitofusin 2 protects hepatocyte mitochondrial function	In vitro (LO2 cell lines)	[59]
Immunomodulation in primary biliary cholangitis with CTLA-4-Ig (immunoglobulin) as an immunotherapeutic agent	Signaling by CTLA-4 can modulate costimulation and induce inhibitory signals	In vivo (murine models)	[60]
Immunomodulation in primary biliary cholangitis with anti-CD40L	Reduced liver inflammation significantly initial lowering of anti-mitochondrial antibodies was observed but non-sustained.	In vivo (murine models)	[61]
Action of nuclear bile acid receptor FXR in cholestasis	Hepatoprotection from cholestasis by inducing FGF-15	In vivo (murine model)	[9]
Immunomodulation Anti-CCR5/CCR2 in combination with all-trans-retinoic acid	Significant reduction in plasma liver enzymes, bilirubin, liver fibrosis, bile duct proliferation and hepatic infiltration of neutrophils and T cells and expression of cytokines	In vivo (murine model)	[62]
Curcumin acts through FXR signaling	Protection against alpha-naphthylisothiocyanate ANIT-induced cholestasis	In vitro and in vivo (murine model)	[63]
Modulation of bile duct proliferation, with Melatonin	GnRH stimulated fibrosis gene expression in Hepatic stellate cells; melatonin may improve outcomes of cholestasis by suppressing GnRH.	In vivo (murine model)	[64]
Apamin, an apitoxin (bee venom) derivate prevented tetrachloride-induced liver fibrosis	Apamin suppressed the deposition of collagen, the proliferation of BECs and expression of fibrogenic genes	In vivo (murine model)	[65]
Toxic bile acids induce mitochondrial fragmentation. Preventing fragmentation improved outcome	Decreasing mitochondrial fission substantially diminished ROS levels, liver injury, and fibrosis under cholestatic conditions	In vivo Knockout mouse models	[66]
Epigenetic approach Histone deacetylase 4 (HDAC4) restores prohibitin-1 (PHB1)	Genomic reprogramming, with regression of the fibrotic phenotype	In vivo Knockout mouse models	[67]
Anti-γ-glutamyl transpeptidase antibody for osteodystrophy in cholestatic liver disease	GGT inhibited mineral nodule formation and expression of alkaline phosphatase and bone sialoprotein in osteoblastic cells.	In vivo (murine model)	[68]
EGFR signaling protects from cholestatic liver injury and fibrosis.	STAT3 is a negative regulator of bile acids synthesis and protects from bile acid-induced apoptosis. Additionally, it regulates EGFR expression	In vivo Knockout mouse models	[69]
Necroptosis pathway in primary biliary cholangitis	Necroinflammatory pathways regulated by receptor-interacting protein 3 (RIP3), with deleterious progress in cholestatic diseases. RIP3 deficiency blocked bile-duct-ligation-induced (BDL) necroinflammation at 3 and 14 d post-BDL	In vivo Knockout mouse models	[70]
Tauroursodeoxycholic acid modulates apoptosis in mice	Significant reduction of liver fibrosis, accompanied by a slight decrease of liver damage	In vivo (murine model)	[71]