Innovative Molecular Target and Therapeutic Approaches in Fatty Liver Disease

Dear Colleagues,  

There is no doubt that both Western and Eastern countries have been affected over the last decade by an obesity epidemic, which is associated with fatty liver disease. This trend is not going to decrease in the following decades. According to histological evidence, steatohepatitis is characterized by a fatty shift, Mallory hyaline, and inflammation. Liver cirrhosis patients, including the patients who have had surgery to alleviate portal hypertension, show a worse chance of survival if Mallory hyaline and fatty alterations are present. Alcoholic liver disease can cause a wide range of liver abnormalities, from fatty changes to cirrhosis and beyond. Macrovesicular fatty alteration is the first and most prevalent sign of alcoholic liver damage. In non-alcoholic steatohepatitis (NASH), the inflammation and fatty alterations are not as commonly found in a centrilobular pattern as they are in alcoholic hepatitis. An abnormal buildup of fat in hepatocytes caused by a metabolic disturbance characterizes NAFLD, which is also not yet definitively called metabolic-associated fatty liver disease (MAFLD). MAFLD is a group of chronic liver illnesses that include a broad range of symptoms, from steatosis and isolated hepatic triglyceride buildup to lipotoxicity and mitochondrial dysfunction, which lead to fibrosis and progressive liver destruction.

Importantly, patients with MAFLD exhibited decreased ATP production, ultrastructural mitochondrial abnormalities, and mitochondrial DNA damage in their liver tissues. Furthermore, increased mitochondrial reactive oxygen species (ROS) reduces mitochondrial membrane potential, causes inflammation, and promotes programmed cell death/apoptosis. It also generates oxidative damage to mitochondrial proteins and DNA. These occurrences cause a decline in liver function. Recently, researchers discovered that patients with MAFLD/MASH had considerably lower markers for hepatic mitochondrial biogenesis, autophagy, fission, and fusion.

Furthermore, it has been discovered that there are linkages between the liver and other organs, such as adipose tissue and the intestine, which adds to the multifactorial nature of MAFLD. No medication that can effectively reverse MAFLD and stop it from progressing to MASH has been approved yet. Phase II and III clinical trials are investigating many compounds; nevertheless, some drugs have demonstrated promise in alleviating inflammation, fibrosis, and steatosis. Improving MAFLD treatment is essential, as is improving its precise diagnosis and monitoring. There is a need for novel, non-invasive ways to better evaluate and track therapy response and disease progression in MAFLD, even if liver histology is still the most reliable way to diagnose and stage the illness, despite remarkable improvements in imaging. The examination of hundreds of molecules has led to the proposal of several classes of molecules, specific proteins, or metabolites thanks to "omics technologies". Key chemicals, such as bile acids and glutathione, whose levels change with the beginning of MAFLD, had their metabolic profiles uncovered using transcriptomics, proteomics, and metabolomics. Several molecular targets for fatty liver disease treatment include receptors in the liver, ARA metabolic enzymes, genetic variants and their CRISPR-Cas9 makeup or remodeling, THR-β, IL-22, and glucagon.  

Since there are currently no satisfactory therapeutic agents for non-alcoholic fatty liver disease (NAFLD), the goal of this Special Issue is to present an update on the diagnosis and treatment of this condition, with the hope of enlightening the molecular targets, which can become innovative therapeutic approaches in a short and medium term. 

We also hope this Special Issue will continue attracting scientists and clinicians to deliver scientific contributions that may help the patients affected by MAFLD/MASH and serve as a basis for starting randomized clinical trials in the near future.  

Prof. Dr. Consolato M. Sergi
Guest Editor

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