Salt-inducible kinase 2b (Sik2b) promotes liver inflammation by phosphorylating BHLHE41 in zebrafish (Danio rerio)

Long-term feeding of palm oil-based diets readily induces inflammatory response in farmed fish, compromising aquaculture efficiency and food safety. Salt-inducible kinase 2 (SIK2), an energy-sensing kinase that orchestrates immunometabolic crosstalk in mammals, may participate in this process. However, little attention has been given to the function of its ortholog in fish. Here, using sik2b knockout zebrafish models together with sik2b knockdown and overexpression experiments in ZFL cells, we found that loss of sik2b induced an anti-inflammatory phenotype in zebrafish hepatocytes, whereas its overexpression elicited inflammatory response. In the feeding trial, sik2b knockout alleviated hepatic injury in zebrafish induced by the complete replacement of fish oil with palm oil. Similarly, in cultured ZFL cells, sik2b knockdown effectively inhibited the expression of inflammatory mediators induced by palmitic acid (PA). Mechanistically, Sik2b interacted with BHLHE41 and phosphorylated it, leading to the cytoplasmic accumulation of BHLHE41, which relieved its transcriptional repression of tnfa, ultimately enhancing tnfa promoter activity. In conclusion, this study uncovered a previously unidentified regulatory role of Sik2b-BHLHE41 signaling axis in hepatic inflammatory response in fish, providing a scientific rationale for the future design of anti-inflammatory targets in aquaculture.