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Non-alcoholic fatty liver disease (NAFLD), recently reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), has become the most prevalent chronic liver disease globally. This reclassification underscores the metabolic dysfunction central to the disease, which spans a spectrum from simple steatosis to more severe forms like steatohepatitis, fibrosis, and cirrhosis. Given the significant overlap between MASLD and type 2 diabetes mellitus (T2DM), the therapeutic strategies for MASLD have increasingly focused on addressing metabolic derangements. Despite its global prevalence, no specific drugs have been approved for MASLD, highlighting an urgent need for effective pharmacological interventions.
Antidiabetic Agents
Given the close association between MASLD and T2DM, antidiabetic medications have been extensively explored as potential therapies. This category includes glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and thiazolidinediones. GLP-1 agonists, such as liraglutide and semaglutide, have shown promise in reducing hepatic steatosis and inflammation by lowering body weight and insulin resistance. Tirzepatide, a dual GLP-1/GIP agonist, has demonstrated a substantial reduction in liver fat and inflammation, positioning it as a potential MASLD therapy. However, while these agents improve metabolic parameters, their long-term efficacy in preventing fibrosis progression remains under investigation.
Targeting Hepatic Lipid Accumulation
Hepatic lipid accumulation is a key driver of MASLD pathogenesis. Therapeutic strategies targeting this pathway include peroxisome proliferator-activated receptor (PPAR) agonists, bile acid-farnesoid X receptor (FXR) agonists, and de novo lipogenesis (DNL) inhibitors. PPAR agonists, such as pioglitazone and elafibranor, have shown efficacy in improving liver histology but are associated with side effects like weight gain. FXR agonists, including obeticholic acid (OCA), have demonstrated significant histological improvements, although concerns about pruritus and adverse cardiovascular effects have tempered enthusiasm. Meanwhile, DNL inhibitors like aramchol have shown potential in early trials, though further studies are needed to confirm their long-term benefits.
Targeting Oxidative Stress, Inflammation, and Fibrosis
Oxidative stress, inflammation, and fibrosis are pivotal in MASLD progression. Antioxidants such as vitamin E, anti-inflammatory agents like emricasan, and antifibrotic drugs like cenicriviroc are being explored for their potential to mitigate these processes. While these agents have shown varying degrees of success in clinical trials, their impact on long-term outcomes remains uncertain. The combination of these agents with other therapeutic strategies may enhance their efficacy and reduce side effects.
Gut Microbiota and Enterohepatic Axis
The gut-liver axis plays a crucial role in MASLD pathogenesis, making it a target for emerging therapies. Agents like IMM-124e, which targets gut microbiota, and solithromycin, a novel macrolide antibiotic, are under investigation for their potential to modulate this axis. Although these approaches are in the early stages of clinical development, they represent a promising avenue for MASLD treatment.
Combination Therapies
Given the complex and multifactorial nature of MASLD, combination therapies targeting different pathogenetic pathways may offer a more effective approach. Such combinations could potentially enhance therapeutic efficacy while minimizing side effects. Ongoing clinical trials are exploring various combinations of antidiabetic agents, PPAR agonists, FXR agonists, and other novel compounds.
Conclusions
MASLD represents a significant and growing public health challenge, with no currently approved pharmacotherapies. However, the expanding pipeline of drug candidates targeting various aspects of MASLD pathogenesis offers hope for effective treatments. As research progresses, it is likely that combination therapies will play an increasingly important role in managing this complex disease, offering new hope to patients at risk of advanced liver disease and its complications.
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The study was recently published in the Journal of Clinical and Translational Hepatology.
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