Novel therapeutic targets in liver pathology: From basic science to clinical translation

The liver is the key organ that has versatile tasks in the body. It is involved in the production and metabolism of many biological compounds (e.g., amino acids and bile), filters the blood, regulates blood clotting, stores vitamins and minerals, processes glucose, and controls fat metabolism. In addition, it is an essential organ contributing to immune system homeostasis by detecting and clearing pathogens entering the body via the gut. However, genetic disorders, alcohol abuse, drugs, cholestasis, metabolic disorders, nutrient overload, and viral as well as parasitic infections can provoke liver injury. Chronic liver disease is associated with profound inflammation leading to fibrosis, cirrhosis, or even hepatocellular carcinoma (HCC). In all these stages, critical cellular and soluble mediators act as potent pathogenic factors promoting disease progression. In particular, the global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) representing a more serious stage of NAFLD are now recognized as the most prevalent chronic liver disease worldwide. Although the knowledge of the pathogenesis of hepatic lesions has steadily increased during the last decades, the respective diseases and connected complications are associated with substantial medical and economic burden worldwide. In this special issue entitled “Novel therapeutic targets in liver pathology: From basic science to clinical translation,” basic researchers and clinicians have compiled 10 articles highlighting novel findings and current biochemical concepts in basic and clinical liver research. These include basic studies on mediators driving hepatic disease, pathways involved in the pathogenesis of NAFLD and HCC, potential biomarkers indicating hepatic dysfunction, and strategies that might be useful to arrest or even reverse hepatic lesions (Figure 1). Sruthi and Raghu examined the effect of methylglyoxal that is formed as a side‐product of several metabolic pathways in the promotion of cancer features in cultured HepG2 cells. The authors could demonstrate that this compound weakened the innate detoxification system, increased the formation of methylglyoxal adducts, advanced glycation end products (AGE), and its receptor (RAGE). Furthermore, glucose uptake, activity of glycolytic enzymes, formation of reactive oxygen species (ROS), and the expression of hypoxia‐inducible factor 1α (HIF1α) were elevated. These results provide strong evidence that methylglyoxal triggers the Warburg effect in HepG2 cells, which is a hallmark of cancer. In an original research article, Peschl and colleagues investigated the expression and function of bone morphogenetic protein 13 (BMP13) in murine models of hepatic fibrosis and in cultured activated hepatic stellate cells that is a suitable model to investigate processes leading to increased synthesis of extracellular matrix compounds. The authors could demonstrate that BMP13 is a profibrogenic factor that is increasingly expressed in hepatic fibrosis and a potential molecular target for the establishment of novel antifibrogenic therapies. The pathogenesis of NAFLD/NASH is rather complex. Vachher et al. reviewed the role of adipokines, hepatokines, and myokines in the pathogenesis of respective diseases and their progression to HCC. Their article demonstrates that this group of soluble mediators that are commonly known as organokines are highly pleiotropic molecules that can produce beneficial and harmful effects on inflammation, oxidative stress, glucose and lipid metabolism, fat distribution, and cancer formation in the setting of NAFLD/NASH and progression to HCC through various paracrine, autocrine, and endocrine pathways. The authors conclude that better knowledge of these activities will be the basis for the development of novel therapeutic strategies and tools for early diagnosis of respective diseases. The contribution by Flessa and colleagues provides an up‐to‐date overview of the significance of endoplasmic reticulum (ER) stress signaling on NAFLD pathogenesis and the current view on how this knowledge can be used to establish novel therapeutic concepts. This review underpins the notion that ER stress can be induced by many different factors including dysfunction of ER homeostasis, disturbance of ER‐mitochondria interaction, excess lipid accumulation, and circadian clock machinery dysregulation. Mir and colleagues compiled a current overview of the contemporary understanding of biomarkers useful for monitoring, diagnosis, and prognosis prediction in