Recent Advancements in Antifibrotic Therapies for Regression of Liver Fibrosis

Abstract

Cirrhosis is a severe form of liver fibrosis that results in the irreversible replacement of liver tissue with scar tissue in the liver. Environmental toxicity, infections, metabolic causes, or other genetic factors including autoimmune hepatitis can lead to chronic liver injury and can result in inflammation and fibrosis. This activates myofibroblasts to secrete ECM proteins, resulting in the formation of fibrous scars on the liver. Fibrosis regression is possible through the removal of pathophysiological causes as well as the elimination of activated myofibroblasts, resulting in the reabsorption of the scar tissue. To date, a wide range of antifibrotic therapies has been tried and tested, with varying degrees of success. These therapies include the use of growth factors, cytokines, miRNAs, monoclonal antibodies, stem-cell-based approaches, and other approaches that target the ECM. The positive results of preclinical and clinical studies raise the prospect of a viable alternative to liver transplantation in the near future. The present review provides a synopsis of recent antifibrotic treatment modalities for the treatment of liver cirrhosis, as well as a brief summary of clinical trials that have been conducted to date.

Treatment of Liver Fibrosis: A 20-Year Bibliometric and Knowledge-Map Analysis

“…In certain animal experiments, removing the causative agents resulted in cirrhosis regression ( Ramachandran and Iredale, 2009 ). Effective fibrolysis requires the targeting of several mechanisms, including 1) ECM degradation, 2) myofibroblast deactivation, 3) hepatocyte regeneration, and 4) vascular and parenchymal remodeling ( Jangra et al, 2022 ). For example, liver injury initiates the transdifferentiation of quiescent HSCs to their activated phenotype characterized by specific phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling.…”

“…During the resolution of hepatic fibrosis, activated HSCs can be cleared by apoptosis or reversion to an inactivated phenotype ( Tsuchida and Friedman, 2017 ). As for different etiological and symptomatic treatments, the corresponding drug targets were concluded as follows ( Friedman, 2015 ; Yoon et al, 2016 ; Odagiri et al, 2021 ; Jangra et al, 2022 ): 1) NASH: pan-caspase inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, pirfenidone, fibroblast growth factor 21 (FGF21), lipid-lowering agents, stearoyl-coenzyme A desaturase 1 (SCD1) inhibitors, thyroid hormone receptor-β (THR-β) agonists, and FGF 19 analogs; AIH: corticosteroids, C-C chemokine receptors 2 and 5 (CCR2/CCR5) inhibitors, galectin-3 inhibitors; PBC: urso deoxycholic acid (UDCA). 2) HBV and HCV: tenofovir, entecavir, interferon, direct-acting antivirals (DAAs); Reduction of fibrotic scar evolution: lysyl oxidase-like 2 (LOXL2) inhibitors and heat shock protein 47 (HSP47) siRNA.…”

Recent evaluation about inflammatory mechanisms in nonalcoholic fatty liver disease

“…During ER stress, mitochondrial ROS production increases, and Ca 2+ leaked from the ER is taken up by mitochondria. Ca 2+ uptake leads to the release of cytochrome C, which further eliminates the electron transport chain function and leads to increased ROS overproduction ( Jangra et al, 2022 ).…”

Liver resection as a stimulation of its regeneration in chronic diseases

“…На сьогоднішній день з різним ступенем успіху було випробувано широкий спектр антифіброзних методів лікування. Ці методи лікування включають використання факторів росту, цитокінів, мікро РНК, моноклональних антитіл, підходи на основі стовбурових клітин та інші підходи, націлені на позаклітинний матрикс [9].…”