Loss of Ambp ameliorates steatosis progression by activating PPARα signaling in zebrafish

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent and serious hepatic disorder affecting approximately 30% of the global population. Despite its high prevalence, the precise pathophysiological mechanisms underlying MASLD development remain incompletely understood. Previous studies have shown that A1M regulates endoplasmic reticulum stress and oxidative responses in hepatocytes, thereby influencing liver homeostasis. However, the roles of AMBP, the precursor of both A1M and Bikunin, in MASLD pathogenesis and progression remain poorly characterized. Here, we generated ambp knockout (ambp^-/-) zebrafish, subjected them to a high-fat diet (HFD), and found that loss of ambp attenuated the development of MASLD under HFD feeding. Mechanistically, Ambp deficiency induced the production of reactive oxygen species (ROS) at homeostatic levels, which subsequently activated the peroxisome proliferator-activated receptor α (PPARα) signaling pathway, which suppressed oxidative stress and maintained lipid homeostasis. Collectively, our results demonstrate that Ambp is a critical regulator of MASLD pathogenesis, suggesting that inhibiting AMBP function represents a potential therapeutic strategy for MASLD treatment.