Aspartate treatment ameliorates metabolic dysfunction-associated fatty liver disease through upregulation of CBS and suppression of ferroptosis.

Dysregulation of non-essential amino acids (NEAAs) contributes to metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Aspartate (ASP), an NEAA serving as a critical precursor for purine, asparagine, and arginine biosynthesis, exhibits unexplored pathophysiological significance in MAFLD. Mass spectrometry profiling identified hepatic ASP as the sole NEAA consistently depleted in both human patients with MAFLD and animal models. Dietary or orally administered ASP supplementation in mice significantly improved insulin sensitivity, suppressed de novo lipogenesis, and enhanced mitochondrial respiration, collectively ameliorating diet-induced MAFLD. Integrative multi-omics analyses revealed that ASP activates the trans-sulfuration pathway through cystathionine β-synthase (CBS) upregulation in hepatocytes, thereby attenuating ferroptosis-evidenced by elevated glutathione and reduced lipid peroxidation. Crucially, pharmacological ferroptosis inhibition (liproxstatin-1) abolished ASP-mediated hepatic improvements, while CBS blockade completely abrogated ASP's therapeutic effects. These findings establish ASP as a novel ferroptosis inhibitor with therapeutic promise for MAFLD.