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["Strategy_ID","Therapy_Strategy","Synonyms","Related_Targets","Related_Drugs","Mechanism","Reference_PMIDs","Update"]
[1,"Improve insulin resistance","insulin sensitizer; insulin resistance; glucose tolerance; glycemic control; glucose-lowering","Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist","Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide","T2DM results from multiple organ abnormalities and various pathophysiological abnormalities. It has been linked to insulin resistance and obesity, indicating that T2DM and NAFLD have similar pathophysiological underpinnings. Therapeutic concepts such as thiazolidinediones (glitazones) for treating T2DM also show some efficacy in the treatment of NASH.","27729660; 32044314","2022-03-21"]
[2,"Enhance lipid metabolism","triglyceride-lowering; lipid tolerance; lipid metabolism","3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor","Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol;","Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.","29936596","2022-03-21"]
[3,"Anti-fibrosis","fibrosis","Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant","Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282","Fibroblast growth factor (FGF) 1 demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.","32965675; 25935633","2022-03-21"]
[4,"Anti-oxidative stress","oxidative stress","α-tocopherol: antioxidant","Vitamin E","Disturbances in lipid metabolism lead to hepatic lipid accumulation, which affects different reactive oxygen species (ROS) generators, including mitochondria, endoplasmic reticulum, and NADPH oxidase. Mitochondrial function adapts to NAFLD mainly through the downregulation of the electron transport chain (ETC) and the preserved or enhanced capacity of mitochondrial fatty acid oxidation, which stimulates ROS overproduction within different ETC components upstream of cytochrome c oxidase.","32156524","2022-03-21"]
[5,"Anti-inflammatory","inflammatory","Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor","Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib;","The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury.","33578800","2022-03-21"]
[6,"Regulating intestinal flora","intestine gut microbiota; gut microbiota","farnesoid X receptor (FXR); fibroblast growth factor-19 (FGF19)","Probiotics; Prebiotics; Rifaximin; Yaq-001; Cilofexor; EDP-305; EYP001a; INT-767","An altered microbiome (“dysbiosis”) may contribute to liver damage. Human studies document a fecal microbiome signature characterized by increased Proteobacteria and Bacteroidetes along with a decrease in Firmicutes in patients with obesity and NASH.","28257306; 28774887","2022-03-21"]
[7,"Anti-lipogenesis","de novo lipogenesis; de novo lipogenesis; DNL;  anti-lipogenic mechanisms; adipogenesis; anti-obesity","stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor","Aramchol; Firsocostat (GS-0976);  VK-2809; ION 224","Those with NAFLD have increased synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFAs and did not suppress the contribution from de novo lipogenesis on fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD. Increased de novo lipogenesis is one of the distinguishing features of NAFLD. This indicates that lipogenesis can be a therapeutic target for NAFLD. Proteomic analysis of the Blnc1 ribonucleoprotein complex identified EDF1 as a component of the LXR transcriptional complex that acts in concert with Blnc1 to activate the lipogenic gene program. These findings illustrate a lncRNA transcriptional checkpoint that licenses excess hepatic lipogenesis to exacerbate insulin resistance and NAFLD.","24316260; 30061575","2022-03-30"]
[8,"Lifestyle measures","Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications;  Exercise",null,null,"Many studies exist that analyzed the effects of lifestyle and weight loss on NAFLD and the risk of subsequent NASH, including MRI spectroscopy studies. Results in overweight patients with biopsy-proven NAFLD could confirm initial findings, also offering the opportunity to assess important changes in inflammation, lobular changes, and fibrosis. Improvements in lifestyle can have immediate and sometimes significant effects on the liver in NAFLD patients, and may contribute to the high rate of ‘placebo response’ observed in NASH trials.","20664019; 28862886","2022-03-30"]
[9,"Bariatric surgery","Metabolic surgery",null,null,"Metabolic surgery reduces ectopic fat, hepatic fat in particular, contributing to a marked improvement of NAFLD/NASH manifestations.","31754142; 22939560","2022-03-30"]
[10,"Liver transplantation",{"$nulls":3},"NASH-associated cirrhosis is to date among the top three indications for liver transplantation in most high-income countries, with the alarming trajectory to become the most common. Outcomes at 1, 3, and 5 years for patients undergoing a liver transplant for NASH-associated cirrhosis are substantially similar to those for other indications.","24076414","2022-03-31"]
[11,"Anti-hypertensive",null,"angiotensin converting enzyme inhibitors (ACEi) ; angiotensin II receptor blockers (ARBs)","Captopril","The renin-angiotensin system is involved in hepatic fibrosis through activation of hepatic stellate cells, major fibrogenic cells in the liver. Hepatic stellate cells are activated by liver injury to express excessive matrix proteins and profibrogenic cytokines such as transforming growth factor-beta 1. There is a significant relationship between inheritance of high transforming growth factor (TGF)-beta1 and angiotensinogen-producing genotypes and the development of progressive hepatic fibrosis in patients with chronic hepatitis C.","17518368；11438504","2022-03-31"]
[12,"Anti-platelet aggregation",null,"Platelet GPIbα","aspirin/clopidogrel; ticagrelor","Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis.","30936549","2022-03-31"]
[13,"Anti-apoptosis","hepatocyte apoptosis; hepatic autophagy; apoptosis","Pan-caspase inhibitor","Emricasan","Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH.","29991872","2022-03-31"]
[14,"Digital therapeutics","Internet-based approach; Web-Based Exercise; Mobile Technology; Mobile APP",null,null,"With the help of the Internet technology, digital therapeutics overcome these disadvantages and has achieved a certain clinical effect in NAFLD patients. A web-based intervention may be better suited for young, busy patients, and for those living far from liver units. Lifestyle intervention enabled by a mobile app can be effective in improving anthropometric indices and liver enzymes in patients with NAFLD. Clinical trial number: NCT02526732.","30290973; 30602434; 31342533; 32281943; 33939147","2022-05-06"]
[15,"Cell therapy","Mesenchymal stem cells; Stem cell therapy",null,null,"Mesenchymal stem cells (MSCs) have the potential for self-renewal and differentiation into multiple cell lineages, including hepatocytes. The migration and engraftation of MSCs into targeted lesions may exert clinical efficacy, such as the improvement of liver fibrosis in patients with NASH.","35123561","2022-05-06"]
[16,"Immunotherapy",{"$nulls":3},"NASH is one of important drivers of hepatocellular carcinoma (HCC), and immunotherapy is considered to activate T cells or reinvigorate immune surveillance against cancer, with a response rate of 15-30% in patients with HCC.","33762733","2022-05-06"]
[17,"Genetic therapy","Genetic approaches; genetherapy; Gene therapy","HSD17B13 inhibitor; PNPLA3-rs7 38409 (I148M) variant inhibitor; PNPLA3 expression down-regulator","INI-678; Momelotinib","Particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments.","32298765","2022-05-06"]