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To explore the effect of concentrated dephenolic cottonseed protein (CDCP) partly instead of fish meal on the non-specific immune of Penaeus monodon, we designed a single factor test to study the four types of non-specific immunity of P. monodon hepatopancreas after acute salinity stress. A total number of 5,400 P. monodon were selected with an initial body weight of 1.76±0.15g and randomly divide into 6 groups (3 replicates per group, 900 tails per replicate). Shrimp were feed with two protein level diets (Diet A and Diet B). After 8 weeks of feeding, P. monodon were randomly selected with an average weight of 14.71±1.06g in each feed group, and subjected to acute salinity stress of 10ppt and 20ppt after temporary rearing, and the heat shock protein 70 (HSP70), Na+-K+-ATPase, cortisol and the content of alkaline phosphatase (ALP) were measured. The results of the study showed that when the CDCP partially replaced fish meal of P. monodon diet, the hepatopancreas HSP70, and the contents of Na+-K+-ATPase and cortisol were significantly higher than those of the control group. In the acute salinity change, there was no significant difference in the survival rate of P. monodon at 48h under the two salinity stresses, and the four immune indexes showed different trends. The expression level of Cortisol was more prominent than that of HSP70, which could better reflect the stress degree of P. monodon. Most of the indicators showed a trend of rising and then falling and then rising compared with the original level, and the changes of the four indicators of hepatopancreas in the Diet B group were significantly higher than those in the Diet A group at most time point of the two salinities.