Pharmacological Interventions for Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders characterised by excessive lipid accumulation in hepatocytes, progressing in some patients to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Lifestyle modification remains the cornerstone of management but is often insufficient or poorly sustained. Pharmacological strategies under investigation target key pathogenic mechanisms, including dysregulated lipid and glucose metabolism, inflammatory signalling and fibrogenesis. Nuclear receptor agonists such as farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) modulators aim to restore metabolic homeostasis, whereas small-molecule inhibitors of stress kinases and novel receptor agonists refine anti-inflammatory and anti-fibrotic responses. Emerging therapies exploit enterohepatic signalling and the gut–liver axis, with potential to address both hepatic and extrahepatic complications such as cardiovascular disease. Taken together, these interventions hold promise for a tailored, mechanism-based approach to NAFLD, with the ultimate goal of improving long-term liver outcomes and reducing metabolic comorbidities.

Research from Nature Portfolio

Recent clinical trials have underscored the therapeutic potential of FXR agonism in reducing hepatic steatosis and enzyme markers. In a phase 2 adaptive study, a novel FXR agonist achieved dose-dependent reductions in alanine aminotransferase and hepatic fat fraction over 12 weeks, with sustained benefits at 48 weeks despite pruritus as a common adverse event. Building on this, pan-PPAR activation has been evaluated in patients with metabolic dysfunction-associated steatohepatitis, demonstrating simultaneous improvements in liver histology, triglycerides, insulin resistance and systemic inflammation. Importantly, adiponectin increases correlated with both hepatic and cardiometabolic benefits, suggesting that PPAR modulation may confer cardiovascular protection alongside histological resolution of NASH. These studies exemplify how targeted nuclear receptor agonists can deliver multi-organ benefits by reprogramming lipid and glucose metabolism within hepatocytes and adipose tissue.

Pharmacological Interventions for Non-Alcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in pharmacological interventions for non-alcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Non-alcoholic fatty liver disease (NAFLD): Spectrum of liver disease characterised by hepatic lipid accumulation in the absence of significant alcohol intake.

Non-alcoholic steatohepatitis (NASH): Progressive form of NAFLD featuring hepatocellular injury, inflammation and varying degrees of fibrosis.

Farnesoid X receptor (FXR): Nuclear receptor that regulates bile acid synthesis, lipid metabolism and inflammatory pathways.

Peroxisome proliferator-activated receptor (PPAR): Family of nuclear receptors involved in the control of lipid and glucose homeostasis, with isoforms α, δ and γ.

Glucagon receptor (GCGR): G-protein-coupled receptor that mediates glucagon’s effects on hepatic glucose and lipid metabolism.

Apoptosis signal-regulating kinase 1 (ASK1): Mitogen-activated protein kinase kinase kinase (MAP3K) involved in stress-induced inflammatory and fibrotic signalling.

Sodium glucose co-transporter 2 (SGLT2): Renal transporter targeted by inhibitors to lower blood glucose and indirectly improve hepatic metabolism.

Glucagon-like peptide-1 (GLP-1): Incretin hormone analogue that enhances insulin secretion, promotes weight loss and exerts anti-inflammatory effects.

References

1. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nature Medicine (2023).
2. The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis. Nature Communications (2024).
3. CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects. Advanced Science (2024).
4. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology (2018).
5. Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD). Frontiers in Endocrinology (2023).