- 2026-02
- European journal of clinical investigation 56(2)
Study Design
- Type
- Systematic Review
- Sample size
- n = 1,671
- Population
- pre-clinical models (in vivo/in vitro) and clinical studies with MASLD (approximately 1671 participants)
- Methods
- Systematic review following PRISMA 2020 guidelines, searching PubMed, Embase, SCOPUS up to December 1, 2025
Introduction
While hyperammonemia is traditionally associated with decompensated cirrhosis, emerging evidence suggests that disturbances in nitrogen homeostasis contribute to disease progression in earlier stages of steatohepatitis and fibrosis. L-ornithine L-aspartate (LOLA), an established ammonia scavenger, targets key pathophysiological mechanisms shared by metabolic dysfunction-associated steatotic liver disease (MASLD), including oxidative stress, mitochondrial dysfunction and hepatic stellate cell activation. This systematic review synthesizes current experimental and clinical research to evaluate the potential therapeutic role of LOLA in MASLD.Methods
A systematic search of PubMed, Embase and SCOPUS was conducted up to December 1, 2025, following PRISMA 2020 guidelines. Eligible studies included experimental (in vivo/in vitro) and clinical trials evaluating the effects of LOLA or L-aspartate on hepatic steatosis, inflammation, or fibrosis in the context of MASLD. Data extraction and quality assessment were performed independently by two reviewers using appropriate tools for animal and human studies.Results
Nineteen studies were included, comprising 10 experimental pre-clinical models (9 in vivo animal studies and 1 in vitro study) and 9 clinical studies involving approximately 1671 participants. Experimental studies consistently demonstrated that LOLA intervention ameliorates hepatic steatosis, inflammation and collagen deposition. Identified molecular mechanisms included the activation of the LKB1-AMPK axis, restoration of mitochondrial bioenergetics and modulation of the gut-liver-muscle axis. In clinical studies, results from three randomized controlled trials (RCTs) indicated significant improvements in liver enzymes (ALT, AST) and lipid profiles, with reductions in hepatic steatosis. Evidence from six observational and open-label studies corroborated these biochemical improvements and further demonstrated significant reductions in blood ammonia levels, improved intrahepatic microcirculation and reduced liver stiffness and patient-reported fatigue. However, clinical evidence remains limited by study heterogeneity and a lack of large-scale randomized trials using specific MASLD criteria.Conclusions
Preclinical evidence suggests that LOLA exerts pleiotropic hepatoprotective effects in MASLD by targeting hyperammonemia-induced fibrosis and metabolic dysregulation. While growing clinical data indicate benefits in biochemical normalization, structural improvement and symptom relief, further robust clinical research is required to validate these findings and establish LOLA as a standard therapeutic option for MASLD patients.
Research Insights
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