Advances in pharmacotherapy of NASH

 Corresponding author: Durga Devi Surya Kumar Verma Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Advances in pharmacotherapy of NASH Durga Devi Surya Kumar Verma * Department of Pharmacology, Jawaharlal Institute of Postgraduate and Medical Education Research (JIPMER) Puducherry. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 318-322 Publication history: Received on 13 July 2025; revised on 20 August 2025; accepted on 22 August 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.23.2.0767 Abstract Recent advances in the pharmacotherapy of Non-Alcoholic Steatohepatitis (NASH) have made significant strides towards addressing this complex. NASH, characterized by hepatic steatosis, inflammation, and fibrosis, can progress to cirrhosis and liver-related complications, highlighting the urgent need for effective treatments. Currently, no FDA-approved therapies exist, but the pipeline for NASH drugs is robust, with several promising candidates under investigation. Key developments include the emergence of targeted therapies such as FXR agonists (e.g., obeticholic acid), PPAR agonists (e.g., elafibranor, lanifibranor), GLP-1 receptor agonists (e.g., semaglutide), and ACC inhibitors (e.g., firsocostat). These drugs aim to address specific pathways involved in NASH pathogenesis, including metabolic dysfunction, inflammation, and fibrosis. Also, the concept of combination therapy is gaining traction, with the potential to more effectively manage the multifactorial nature of NASH by simultaneously targeting multiple disease mechanisms. Progress in identifying non-invasive biomarkers (cytokeratin 18) and imaging techniques (USG, MRI, MRE) has also enhanced the ability to monitor disease progression and treatment response, reducing reliance on liver biopsies. However, challenges remain, including ensuring the safety and tolerability of these therapies, managing patient heterogeneity, and addressing the regulatory hurdles that complicate drug approval, hence advances hope for effective treatment options in the near future. Keywords: Resmeritom; Genetic factor; Pioglitazone; Liraglutide; Vitamin E; Polyphenols 1. Introduction A type of liver disease in which fat builds up in the liver of people who drink little or never had taken alcohol in any part of their life. In Nash patients usually suffer from inflammation of the liver, damage to the cells in the liver, which lead to cirrhosis (scarring of liver) and liver failure. It is more common in the middle-aged population. It is also known as MASH. It is manifested as metabolic syndrome; its development and progression are influenced by complex interaction of environmental and genetic factors. Metaanalytic pooling of NAFLD overall global prevalence is 30.05% and 30.69%1, 2. Cardiovascular diseases, metabolic syndrome, obesity, Type II Diabetes mellitus, Dyslipidemia, smoking, diet, gut microbiota, physical activity are the major risk factor 3. Genetic factor which contributes are, PNPLA3 (Patatin-like phospholipase domaincontaining protein-3), TM6SF2 (Transmembrane 6 superfamily member 2), MBOAT7 (Membrane-Bound-O-Acyltransferase Domain-Containing 7), GCKR (Glucokinase Regulator), HSD17B13 (Hydroxysteroid 17-Beta Dehydrogenase 13), SREBF1 (Sterol Regulatory Element-Binding Protein 1), variation in this gene can also leads to NASH development 4. GeneGene and geneenvironment complex interaction determined the risk of development of NASH. 1.1. Pathophysiology World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 318-322 319 Insulin Resistance, the liver takes up the excess FFAs, leading to triglyceride synthesis and storage causing hepatic steatosis 5, 6. Lipid metabolism dysregulation, De novo lipogenesis (carbohydrates convert to fatty acid) further contributes to hepatic steatosis 7. Toxic lipids such as Diacylglycerol (DAG) and ceramides, disrupt cellular functions of the liver. ROS (reactive oxygen species) and mitochondrial dysfunction increase oxidative stress which can damage cellular components, including lipid, proteins, and DNA8. Inflammation Activation of Kupffer cells, inflammatory signaling pathway including the nuclear factor kappa B (NF-KB) leads to inflammation of hepatocyte causing hepatocyte ballooning 9. Apoptosis, Necroptosis, pyro ptosis significantly contributes to liver injury in NASH. Stellate cell activation, fibrogenesis, TGF-Beta pathway leads to chronic liver injury accumulation of extracellular matrix proteins causing fibrogenesis and fibrosis of liver which may progress to cirrhosis 10. GutLiver axis, alteration to gut microbiota by translocating the bacterial endotoxin like lipopolysaccharide in liver. Reduced adiponectin and elevation of leptin promotes elevation of liver fibrosis 11. Toxic advanced end glycation end product formed through the non-enzymatic Maillard reaction between reducing sugar and carbonyl compound with protein, lipid and nucleic acid, as well as GA produced through the fructose and sucrose metabolism pathway, accumulation led to formation and progression of TAGE in liver. This is strongly associated with the necro-inflammatory process of NASH 12. The hedgehog pathway is a signaling process involved in, diseases development, tissue repair, diseases progression, any deviation in this pathway lead to development of NASH 12. 1.2. Sign and Symptom of NASH Fatigue, abdominal discomfort, weakness, unexplained weight loss, Sign of liver damage Jaundice, spider angioma, palmar erythema, ascites, oedema, hepatomegaly. May Progress to liver disease Portal hypertension, Hepatic encephalopathy, Liver failure 13. 1.3. Current treatment General advice for steatosis liver diseases – Healthy lifestyle and >8-10% weight loss considered for pharmacological and surgical intervention if desired body weight is not reached. Mediterranean diet and dash diet. Management of F0 - F1stage of liver fibrosis lifestyle modification. F2-F3 stages lifestyle modification, consider Resmeritom an FDA approved drug for liver fibrosis. F4 stages of cirrhosis lifestyle modification and cirrhosis-based management. Obesity vitamin E 800 IU/day supplementation, GLP1receptor agonist, SGLT-2 inhibitor and bariatric surgery 14. 1.3.1. Diagnosis Initial assessment includes patient history, physical examination, laboratory test, imaging and histology 15,16. Cytokeratin biomarker 18 hepatocyte apoptosis is a marker available for NASH, commercially not available till now. Epigenetic and mitochondrial DNA as potential biomarkers for disease severity. 17 MicroRNA AND Long non-coding RNA play a role in fibrosis progression through human data. Metabolomics has made differentiation easier for a panel of Triglyceride and other lipids have been identified which is a potential biomarker for NASH. Omics platform integrates multiple biochemical analysis to tackle the complexity of biochemical regulation and enhanced translational research. Non-invasive test USG first line methods for diagnosis of NAFLD (effective only when degree of steatosis is >30%). MRI most sensitive modality for the evaluation of hepatic steatosis (detect as little as 3% steatosis). Transient elastography and Magnetic resonance elastography are other diagnostic tools for detection of NASH 15,18. 1.3.2. New drug Currently approved drug for NAFLD is Resmeritom , improves MASH by increasing hepatic fat metabolism and reducing lipo-toxicity, it works as THR-B agonist whose action is a B-oxidation of mitochondrial, reduced production and secretion of very low-density lipoprotein, free fatty acid uptake and synthesis as well as enhance expression of LDL receptor in the liver, have principal role in drug development for the treatment of dyslipidemia , obesity and hepatic steatosis 14. 1.3.3. Drug Repurposing Pioglitazone (PPAR -Y agonist) is mainly used for type 2-diabetes, now used for NASH treatment, it improves liver histology, reducing steatosis and inflammation 6. Vitamin E has an antioxidant property, scavenge free radical, maintains cell membrane integrity, and has anti-inflammatory properties. PIVENS study showed that a 2-year period for treatment with vitamin E at 800IU/ day significantly reversed steatohepatitis and significantly reduced hepatic steatosis and alanine aminotransferase level, and did not make significant changes in fibrosis compared to placebo 8. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 318-322 320 Liraglutide is a human analogue of the human GLP-1 (Glucagon like peptide) hormones which is naturally secreted by the intestine in response to food intake. Phase -2 trial (52 patients) evaluated liraglutide, a synthetic long-acting glucagon like peptide 1 agonist, found to be effective for the treatment of NASH in terms of weight loss, resolution of steatohepatitis and less progression of fibrosis than placebo 19. Caffeine is a strong antioxidant that could help reduce the oxidative stress and inflammation in the liver and provide hepatoprotective effect. There is an evident protective role of more than 3 cups of coffee consumption per day according to meta-analysis study 20. Polyphenols heterogenous class of plant derived that include several hydro soluble antioxidants reported as a health promoting agent and proposed in the treatment of metabolic disorder. Natural polyphenols have been found in various fruits, vegetables and flowers 21. Statins work by inhibiting HMG CO-A reductase, an enzyme that plays a critical role in the Mevalonate pathway which is responsible for the synthesis of cholesterol in the liver. Inhibiting this enzyme statin effectively reduces the production of cholesterol in the liver. antiinflammatory property potential to reduce liver inflammation and fibrosis in NAFLD 22. Metformin has a primary mechanism in the inhibition of gluconeogenesis. Improve insulin sensitivity by enhancing glucose uptake by these tissues. It also has benefits in NAFLD, inhibiting fatty acid synthesis in the liver, contributing to beneficial effects of liver. SGLT2 inhibitors promote weight loss through caloric loss via glycosuria, thus weight reducing effects of SGLT2 inhibitors help decrease the synthesis and storage of fat in liver, which is a key factor in development of NASH in liver 6. US FDA approved pharmaceutical weight loss agent orlistat, phentermine/ topiramate, liraglutide, lorcasein, NaltrexoneBupropion, can be given in NASH. A prospective cohort study of 261 patients proved that 10% weight reduction has led to 90% complete resolution of NAFLD. The study also suggests that weight loss of more than 10% is associated with fibrosis regression with this effect seen in 45% of patients 10. Gut microbiota plays a critical role through its impact on intestinal barrier integrity and systemic inflammation. Dietary modification, such as an increase in fibre intake especially on plant-based diets, higher abundance of beneficial bacteria, SCFA production and consuming polyphenol rich food offer promising strategies for NAFLD 23. FDA approved hedgehog pathway inhibitor can be a viable therapy of NASH to prevent existing liver fibrosis and progression to cirrhosis. 1.4. Limitation in pharmacotherapy of NASH Complexity of Diseases pathophysiologyNASH is multifactorial in nature, driven by a combination of factors including insulin resistance, lipo-toxicity, oxidative stress, inflammation and fibrosis. Monotherapy is limited efficacious, some drugs may show safety and tolerability issues, and many NASH patients already have some comorbid condition such as diabetes and are on other medical conditions. Emerging therapies are likely to be expensive, potentially limiting their accessibility, especially in lowand middle-income countries where the burden of NAFLD is rising. Need for combination therapies still has an unclear impact on long term outcome. 2. Discussion Advances in pharmacotherapy of NASH is a growing effort to address the complex and widespread liver diseases, characterised by liver inflammation and fibrosis, which can progress to liver cirrhosis, liver failure, or hepatocellular carcinoma. The understanding of NASH pathophysiology proved that it is a Multifactor driven disease. Due to its nature a single therapeutic approach is not sufficient to achieve a therapeutic goal. As the NASH prevalence and our knowledge towards it grows, physicians came to a conclusion that personalized medicine tailored to individual patient profiles will be effective in curing the patient. 3. Conclusion Advances in pharmacotherapy of Non-alcoholic Steatohepatitis have been significant, although challenges remain. Resmeritom has been the only FDA approved drug of therapy for NASH. 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