Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is primarily expressed in macrophages. It functions as a pro-inflammatory cytokine and is involved in various biological processes and diseases. Saa3 can regulate lipid metabolism, influence macrophage differentiation, and participate in inflammatory and fibrotic pathways [1,2]. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying its functions.

In SAKI, Saa3 promotes pro-inflammatory macrophage differentiation, with Saa3hi Ccl2hi monocyte-derived infiltrated macrophages fostering inflammation and interacting with renal cells, suggesting it may be a predictive marker [1]. In Tsc1Dmp1 mice, genetic depletion of Tsc1 in osteocytes/osteoblasts leads to upregulation of Saa3, which binds to TLR4 on hepatocytes, phosphorylates c-Jun, and suppresses Cyp7a1 expression, resulting in cholesterol metabolic dysregulation. Ablation of Saa3 prevents CYP7A1 reduction in the liver and cholesterol elevation in the serum [2]. In the DSS-induced IBD mouse model, SAA3-deficient mice exhibit more severe intestinal fibrosis as SAA3 genetic disruption in fibroblasts enhances cell activation to myofibroblasts through the HSPB1/NF-κB/TGF-β1/Smads signaling cascade [3].

In summary, Saa3 is crucial in inflammation, lipid metabolism, and fibrosis. KO mouse models have revealed its role in sepsis-induced AKI, cholesterol metabolism, and intestinal fibrosis, providing insights into potential therapeutic strategies for related diseases.