Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

Abstract

Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.

Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)

“…Targeting pathways involved in metabolic stress of hepatocytes using GalNAc-coupled siRNA, which has received FDA approval for TTR amyloidosis [142], or by using pharmacological agonists/inhibitors might be a promising approach. Currently, obeticholic acid, a FXR agonist; PPAR agonist namely, Lanifibranor; glucagon-like peptide 1 receptor (GLP1R) agonist Semaglutide, thyroid hormone receptor β (THRβ) agonist Resmetirom and stearoyl-CoA desaturase 1 (SCD1) inhibitor Aramchol are in clinical trials for MAFLD treatment [143,144]. Targeting hepatocytes that initiate the cellular crosstalk to HSCs might provide a promising therapeutic strategy; however, further studies are required to establish the most relevant approaches in this regard.…”

Combined hepatoprotective pharmacotherapy for liver disease

“…Предположительно, ω-3-полиненасыщенные жирные кислоты (ПНЖК) могут обладать синергичным с силимарином действием, направленным преимущественно на уменьшение продукции провоспалительных цитокинов-производных арахидоновой кислоты, а также нейтрализацию активных форм кислорода и стимуляцию регенераторных процессов [106]. В исследовании на животных с метаболическим синдромом такая комбинация значительно более эффективно по сравнению с контролем и монотерапией ПНЖК уменьшала содержание ОХС, ТАГ и свободных высших жирных кислот в плазме крови, накопление ТАГ в периферических мышцах, а также увеличивала уровень восстановленного глутатиона в печени [107].…”

“…Заметим также, что в последние годы проводится активное изучение комбинаций новых и экспериментальных препаратов (например, агонистов фарнезоидных рецепторов) с различными средствами метаболической направленности при НАЖБП [106,132], однако окончательные результаты этих исследований остаются впереди.…”

Helminth infection and helminth-derived products: A novel therapeutic option for non-alcoholic fatty liver disease

“…Moreover, NAFLD is being diagnosed in a growing number of obese children and adolescents ( 5 ). Despite the increasing prevalence of NAFLD, which imposes a health burden on society and a huge economic burden on the medical industry, no medicines are available yet for the treatment of NAFLD ( 6 , 7 ). Therefore, new therapeutic strategies for NAFLD should be explored.…”