Table 1.

Pre-clinical and clinical use of antifibrotic agents in metabolic disease

Pre-clinical studies
Organ	Antifibrotic agent	Experimental model	Phenotype	Reference
Liver	Pirfenidone	• Animal: male mice (concanavalin A-induced liver fibrosis) • Dose: 125 mg/kg/day (2 weeks) • Administration: intraperitoneal	• Reduced expression of type II and IV collagens and α-SMA. • Decreased serum levels of TGF-β, TNF-α, and TIMP1.	[195]
		• Animal: male mice (fibrosis induced by (CCl4)) • Dose: 100/300/600 mg/kg (4 or 14 weeks) • Administration: in diet	• Reduced collagen deposition at 300 and 600 mg/kg pirfenidone. • No effect on inflammation.	[196]
		• Animal: male cirrhotic Wistar rats (fibrosis induced by CCl4 and bile-duct ligation) • Dose: 500 mg/kg per day (3 weeks) • Administration: gastric gavage	• Decreased gene expression of collagens I, III, and IV, TGF-β, Smad-7, TIMP-1, and PAI-1. • Reduced the activation of HSCs.	[197]
	Fluorofenidone	• Animal: male albino Wistar rats (pig serum-induced liver fibrosis) • Dose: 240 mg/kg/day (4 weeks) • Administration: intragastric route	• Decreased collagen I and III and α-SMA at the mRNA and protein levels.	[176]
Heart	Pirfenidone	• Animal: male Wistar rats (streptozotocin-induced diabetes) • Dose: 200 mg/kg/day (4 weeks) • Administration: drinking water (0.2–2 g/L)	• Decreased perivascular and interstitial collagen and attenuated diastolic stiffness.	[169]
		• Animal: male Sprague-Dawley rats (myocardial infracted model) • Dose: 1.2% pirfenidone (4 weeks) • Administration: in diet	• Decreased total and non-scar fibrosis. • Improved LV function.	[171]
		• Animal: male Wistar hypertensive rats (deoxycorticosterone acetate-SALT) • Dose: 250–300 mg/kg/bw (2 weeks) • Administration: in diet	• Normalised collagen deposition and diastolic stiffness.	[170]
		• Animal: male C57BL/6J mice (pressure-overload induced heart failure) • Dose: 400 mg/kg/day (4 weeks) • Administration: gastric gavage	• Inhibited TGF-β mediated collagen I expression in fibroblast cells. • Prevented TGF-β mediated changes in claudin 5 expression in cardiac fibroblast and endothelial cells • Improved LV systolic function	[172]
Adipose tissue	Isoliquiritigenin	• Animal: C57BL/6 mice (high fat diet induced adipose tissue fibrosis) • Dose: 0.5% w/w (20 weeks) • Administration: in diet	• Reduced fibrotic area, TNF-α, COL1, and TGF-β1 expression.	[88]
Skeletal muscle	Nintedanib	• Animal: porcine model (Volumetric muscle loss-induced fibrosis) • Dose: 300 mg/day (30 days) • Administration: gastric gavage	• Reduced fibrosis and muscle stiffness.	[175]
	PEGPH20	• Animal: male C57BL/6J (high fat diet induced skeletal muscle insulin resistance) • Dose: 0.1 and 1 mg/kg (24 days) • Administration: tail vein	• Reduced hyaluronan in muscle ECM. • Increased insulin signalling and muscle vascularization. • Suppressed adipocyte lipolysis and hepatic glucose production.	[3]
Pancreas	PEGPH20	• Animal: genetically engineered pancreatic cancer mouse model • Dose: once weekly (dose not specified) (3 weeks) • Administration: intravenous	• Decreased hyaluronan deposition and reduced interstitial fluid pressure (IFP). • Improveed survival in animals with advanced and metastatic cancer.	[177]
Clinical trials
Organ	Antifibrotic agents	Diseases	Study outcomes	Reference
Liver	Pirfenidone (NCT02161952)	Chronic hepatitis C	• Reduced progression of inflammation, fibrosis, and accumulation of fat in hepatocytes. • Enhanced hepatic expression of the anti-fibrogenic receptor CB2 and decreased serum levels of TGF-β1 and IL-6.	[168]
	Pirfenidone (PROMETEO; NCT04099407)	Advanced liver fibrosis	• Reduction in fibrosis score. • Decreased levels of alanine transaminase (ALT) and/or aspartate aminotransferase (AST), albumin, and serum concentrations of TGF-β, IL-1, and IL-6.	[173]
Heart	Pirfenidone (PIROUETTE; NCT02932566)	Heart failure with preserved ejection fraction (HFpEF)	• Decreased myocardial extracellular volume. • No change in LV diastolic function.	[174]