1Department of Hepatology & Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany. Electronic address: firstname.lastname@example.org.
2Department of Hepatology & Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health, Berlin, Germany.
3NAFLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, San Diego, CA, United States. Electronic address: email@example.com.
4Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address: Scott.Friedman@mssm.edu.
Successful development of treatments for non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH) has been challenging. Because NASH and fibrosis lead to NAFLD progression towards cirrhosis and to clinical outcomes, approaches have either sought to attenuate metabolic dysregulation and cell injury, or directly target the inflammation and fibrosis that ensue. Targets for reducing the activation of inflammatory cascades include nuclear receptor agonists (thyroid hormone receptor-beta, e.g. resmetirom, peroxisome proliferator-activated receptor [PPAR], e.g. lanifibranor, farnesoid X receptor [FXR], e.g. obeticholic acid), modulators of lipotoxicity (e.g. aramchol, acetyl-CoA carboxylase inhibitors) or modification of genetic variants (e.g. PNPLA3 gene silencing). Extrahepatic inflammatory signals from circulation, adipose tissue or gut are targets of hormonal agonists (e.g. glucagon-like peptide-1 [GLP-1] like semaglutide, fibroblast growth factor [FGF]-19 or FGF21), microbiota or lifestyle (weight loss, diet, exercise) interventions. Stress signals and hepatocyte death activate immune responses engaging innate (macrophages, lymphocytes) and adaptive (auto-aggressive T-cells) mechanisms. Therapies seek to blunt immune cell activation, recruitment (chemokine receptor inhibitors) and responses (e.g. galectin 3 inhibition, anti-platelet drugs). The disease-driving pathways of NASH converge to elicit fibrosis, which is reversible. The activation of hepatic stellate cells (HSC) into matrix-producing myofibroblasts can be inhibited by antagonizing soluble factors (e.g. integrins, cytokines), cellular crosstalk (e.g. with macrophages), and agonizing nuclear receptor signaling (e.g. FXR or PPAR agonists). In advanced fibrosis, cell therapy with restorative macrophages or reprogrammed T-cells (e.g., CAR T) may accelerate repair through HSC deactivation or killing, or by enhancing matrix degradation. Heterogeneity of disease - either due to genetics or divergent disease drivers - is an obstacle to defining effective drugs for all patients with NASH that will be incrementally overcome.