Current, emerging, and potential therapies for non-alcoholic steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) has been identified as the most common chronic liver disease worldwide, with a growing incidence. NAFLD is considered the hepatic manifestation of a metabolic syndrome that emerges from multiple factors (e.g., oxidative stress, metabolic disorders, endoplasmic reticulum stress, cell death, and inflammation). Non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, has been reported to be a leading cause of cirrhosis and hepatic carcinoma, and it is progressing rapidly. Since there is no approved pharmacotherapy for NASH, a considerable number of therapeutic targets have emerged with the deepening of the research on NASH pathogenesis. In this study, the therapeutic potential and properties of regulating metabolism, the gut microbiome, antioxidant, microRNA, inhibiting apoptosis, targeting ferroptosis, and stem cell-based therapy in NASH are reviewed and evaluated. Since the single-drug treatment of NASH is affected by individual heterogeneous responses and side effects, it is imperative to precisely carry out targeted therapy with low toxicity. Lastly, targeted therapeutic agent delivery based on exosomes is proposed in this study, such that drugs with different mechanisms can be incorporated to generate high-efficiency and low-toxicity individualized medicine.

Keywords: ferroptosis; lipid peroxidation; metabolic homeostasis; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; targeted therapeutics; the gut microbiome.

FIGURE 1

Targets for correcting metabolic disorders in NASH.

FIGURE 2

Therapeutic strategies of stem cells and their derivatives in NASH. Implantation of stem cells or stem-cell-differentiated cells is used to treat NASH. Additionally, stem cell derivatives are also promising for NASH treatment.

FIGURE 3

Engineered exosomes of targeted drug delivery against NASH. Preparation of engineered exosomes: drugs are to be loaded in the exosomes following exosomal surface modification. The targeting ability of engineered exosomes is enhanced by surface modification. Exosomes targeting cells other than macrophages require CD47 modification. Engineered exosomes taken up by liver sinusoid: infusion of engineered exosomes is used to treat NASH by delivering drugs to targets. Targeting cells other than LSECs and macrophages in therapeutic agents delivery is difficult due to hepatic histological characteristics and LSEC capillarization occurred at the early stage of NAFLD.