Abstract: To investigate the effects of replacing fish meal with intestinal mucosal protein (IMP) on growth performance, serum biochemistry and liver health in hybrid sturgeon(Acipenser baerii♀×A. schrenckii♂). Six isonitrogenous and isolipidic diets were formulated with IMP replacing fish meal protein at 0% (IMP0), 5% (IMP5), 10% (IMP10), 20% (IMP20), 40% (IMP40) and 60% (IMP60). A 60-day feeding trial was conducted using hybrid sturgeon with an initial body weight of (14.00 ± 0.30) g. Multiple detection methods including histomorphology, serum biochemistry, transcriptomics and metabolomics were adopted in this research. IMP replacement below 20% had no significant adverse effects on growth performance. However, replacement above 20% significantly decreased final body weight and specific growth rate, induced hepatic vacuolization, increased serum liver injury marker enzymes, and decreased antioxidant enzyme activities. Transcriptomic analysis revealed that the IMP60 group significantly inhibited the expression of the lipid transport-related gene fabp6, while upregulating the bile acid synthesis rate-limiting enzyme gene cyp7a1 and the key cholesterol synthesis gene hmgcs1. Metabolomic analysis showed that the IMP60 group led to an increase in the contents of bile acid-related substances such as tauroursodeoxycholic acid, and simultaneously activated the arachidonic acid metabolism and neuroendocrine stress pathways. Multi-omics correlation analysis indicated that differential metabolites including tauroursodeoxycholic acid and 15-oxoeicosatetraenoic acid were positively correlated with differential genes such as cyp7a1 and hmgcs1, but negatively correlated with differential genes like fabp10a and gpx4. It suggested that liver injury induced by high-level IMP substitution was potentially associated with bile acid metabolism disorder and inflammatory activation. This study showed that 10% intestinal mucosal protein replacement had no significant negative effects on the growth, liver histology and serum biochemistry of hybrid sturgeon, while high-proportion replacement inhibited growth and induced liver injury, which might be attributed to the combined disruption of bile acid metabolism, inflammation and oxidative stress.