Background: Monosodium glutamate (MSG) is a widely used flavor enhancer whose safety profile has been challenged by numerous preclinical studies reporting hepatotoxic effects. However, significant methodological concerns question the clinical relevance of these findings.

Methods: We conducted a comprehensive review of preclinical and clinical studies investigating MSG-induced liver injury, examining mechanisms of toxicity, study methodologies, regulatory perspectives, and potential protective interventions. Literature was systematically searched using multiple databases, focusing on hepatotoxicity studies published between 1990-2024.

Results: Preclinical studies consistently demonstrate MSG-induced hepatotoxicity through oxidative stress, inflammatory pathways, and mitochondrial dysfunction. However, critical analysis reveals severe methodological limitations: 95% of studies employed doses 10-100 times higher than typical human intake (0.04-8 g/kg vs 4-14 mg/kg/day), with 78% using non-physiological administration routes. The 2017 EFSA re-evaluation established an ADI of 30 mg/kg/day, paradoxically below normal dietary intake levels. Plant-based compounds demonstrate significant hepatoprotective potential through antioxidant and anti-inflammatory mechanisms.

Conclusion: While mechanistic pathways of MSG hepatotoxicity are well-characterized, the clinical relevance remains questionable due to methodological flaws in existing studies. Future research should employ physiologically relevant doses and oral administration to establish meaningful safety parameters for human consumption.

Keywords: Monosodium Glutamate, Hepatotoxicity, Oxidative Stress, Food Safety, Liver Injury, Regulatory Toxicology