Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is an acute-phase reactant synthesized in response to infection, inflammation, and trauma. It plays diverse roles in multiple biological processes, with implications in inflammation-related pathways and lipid metabolism [2,4]. Genetic models, especially KO mouse models, have been crucial in understanding its functions.

In sepsis-induced acute kidney injury (SAKI), Saa3, highly expressed in macrophages, promotes pro-inflammatory macrophage differentiation. Saa3hi Ccl2hi monocyte-derived infiltrated macrophages foster inflammation and interact with renal cells, suggesting Saa3 as a potential SAKI predictive marker [1]. In hypercholesterolaemia, Saa3 produced by osteocytes/osteoblasts binds to TLR4 on hepatocytes, phosphorylates c-Jun, and suppresses Cyp7a1 expression, impeding cholesterol conversion to bile acids. Ablation of Saa3 in Tsc1Dmp1 mice prevents liver CYP7A1 reduction and serum cholesterol elevation [2]. In pancreatic tumors, Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts (CAFs). Saa3-competent CAFs stimulate tumor cell growth, while Saa3-null CAFs inhibit it [3]. In an 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 [4].

In summary, Saa3 has significant functions in inflammation and metabolism-related diseases. Gene-knockout mouse models have revealed its roles in SAKI, hypercholesterolaemia, pancreatic tumorigenesis, and intestinal fibrosis, providing valuable insights into disease mechanisms and potential therapeutic targets.

References:

1. Peng, Yi, Fang, Yan, Li, Zhilan, Liu, Chenxi, Zhang, Weiru. 2023. Saa3 promotes pro-inflammatory macrophage differentiation and contributes to sepsis-induced AKI. In International immunopharmacology, 127, 111417. doi:10.1016/j.intimp.2023.111417. https://pubmed.ncbi.nlm.nih.gov/38134592/

2. Huang, Shijiang, Jiang, Yuanjun, Li, Jing, Bai, Xiaochun, Guo, Bin. 2024. Osteocytes/Osteoblasts Produce SAA3 to Regulate Hepatic Metabolism of Cholesterol. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2307818. doi:10.1002/advs.202307818. https://pubmed.ncbi.nlm.nih.gov/38613835/

3. Djurec, Magdolna, Graña, Osvaldo, Lee, Albert, Guerra, Carmen, Barbacid, Mariano. 2018. Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. In Proceedings of the National Academy of Sciences of the United States of America, 115, E1147-E1156. doi:10.1073/pnas.1717802115. https://pubmed.ncbi.nlm.nih.gov/29351990/

4. Zou, Xiaodong, Wu, Tong, Lin, Jianjiao, Ye, Richard D, Xiang, Li. 2025. SAA3 deficiency exacerbates intestinal fibrosis in DSS-induced IBD mouse model. In Cell death discovery, 11, 25. doi:10.1038/s41420-025-02299-x. https://pubmed.ncbi.nlm.nih.gov/39863585/