Steatotic liver disease and cancer: from pathogenesis to therapeutic targets

As environmental exposomes are changing with time, so are liver diseases around the globe. Due to an increasing prevalence of overnutrition and sedentary lifestyle in the global population, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis have been increasing steadily in the past decades. Alcohol consumption is another common risk factor for liver diseases such as alcohol-associated liver disease or hepatitis. For both alcohol-associated and metabolic dysfunction-associated liver diseases, hepatocyte injuries are among the early events during the development of steatotic liver disease (SLD). Hepatic inflammation and fibrosis ensue with recurring hepatic damages owing to immune responses from multiple immune cell types, particularly neutrophils, Kupffer cells and monocyte-derived macrophages in response to damage-associated and pathogen-associated molecular patterns, and extracellular matrix production predominantly from hepatic stellate cells. Both environmental and genetic factors contribute to the SLD pathogenesis. Common environmental risk factors include obesity, type 2 diabetes mellitus, unhealthy diets, sedentary lifestyle and excessive alcohol consumption. Numerous genome-wide association studies have identified multiple genetic variants associated with key traits of SLD, including patatin-like phospholipase domain containing 3 rs738409, transmembrane 6 superfamily member 2 rs58542926, membrane bound O-acyltransferase domain containing 7 rs641738 and hydroxysteroid 17 beta-dehydrogenase 13 rs72613567. Cirrhosis and liver cancer are common late-stage developments of various chronic liver diseases; however, there are pathological differences according to disease aetiologies. Therefore, preventive and therapeutic intervention strategies should align with the underlying causal and modifiable factors. Currently, multiple therapeutics have been developed or approved for treatment of SLD, including thyroid hormone receptor β agonists, glucagon-like peptide 1 receptor agonists and fibroblast growth factor 21 analogues. The concept of this review was motivated and inspired by the Seventh Annual Symposium of Chinese American Liver Society held in San Diego, California, USA on 13-14 November 2024.