Spp1, also known as osteopontin (OPN), is a multifunctional secreted phosphorylated glycoprotein. It is expressed in several cell types such as osteoblasts, fibroblasts, macrophages, and cancer cells. Spp1 is involved in multiple biological processes, including immune-related responses, cell-cell communication, and may be associated with various signaling pathways like STAT3, NF-κB, and others [1,4,5,6].

In non-alcoholic steatohepatitis (NASH), conditional knockout (CKO) of Spp1 in myeloid cells (Spp1ΔMye) worsened NASH, while conditional knockin (CKI) of Spp1 in myeloid cells (Spp1KI Mye) or hepatic macrophages (Spp1KI LvMF) conferred protection. The protection was mediated by upregulation of oncostatin-M (OSM) which increased arginase-2 (ARG2) through STAT3 signaling, enhancing fatty acid oxidation (FAO) in hepatocytes [1]. In idiopathic pulmonary fibrosis, SPP1hi macrophages were found to be highly proliferative and contributed to lung fibrosis, suggesting a role for Spp1 in fibrotic processes [2]. In fibrosis after heart and kidney injury, platelet-instructed Spp1 + macrophages drove myofibroblast activation in a CXCL4-dependent manner, and loss of Cxcl4 abrogated profibrotic Spp1 macrophage differentiation and ameliorated fibrosis [3].

In conclusion, Spp1 plays crucial roles in multiple disease conditions. The use of gene knockout and conditional knockout mouse models has revealed its importance in NASH, fibrosis, and potentially other diseases. These studies help understand the biological functions of Spp1 in immune-related and fibrotic processes, providing potential therapeutic targets for these diseases.