Spp1, also known as osteopontin (OPN), is a multifunctional secreted phosphorylated glycoprotein. It is expressed in various cell types like osteoblasts, fibroblasts, macrophages, and is involved in numerous biological processes and disease-related pathways [7].

In non-alcoholic steatohepatitis (NASH), conditional knockout (CKO) of Spp1 in myeloid cells (Spp1ΔMye) worsened NASH, while conditional knockin (CKI) in myeloid cells (Spp1KI Mye) or hepatic macrophages (Spp1KI LvMF) conferred protection. The protection was mediated by induction of arginase-2 (ARG2) via oncostatin-M (OSM)-STAT3 signaling, enhancing fatty acid oxidation (FAO) in hepatocytes [1]. In idiopathic pulmonary fibrosis, SPP1hi macrophages showed highly upregulated SPP1 and MERTK expression, and their proliferation contributed to lung fibrosis [2]. Platelet-instructed Spp1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner, and loss of Cxcl4 abrogates profibrotic Spp1 macrophage differentiation and ameliorates fibrosis [3]. In Alzheimer's disease mouse models, absence of Spp1 expression prevented synaptic loss as perivascular SPP1 is required for microglia to engulf synapses [4]. In colorectal cancer, SPP1+ macrophages promote metastasis [5]. In vascular calcification, SPP1+ macrophages play an important role [6]. In lung adenocarcinoma, SPP1 expression on tumor-associated macrophages (TAMs) is correlated with poor prognosis and chemoresistance [7]. In melanoma, SPP1 was identified as a driver and a crucial target of BET inhibitors, and silencing SPP1 suppressed melanoma cell proliferation, migration, and invasion [8]. In gastric metastatic cancer, the crosstalk between SPP1+ TAMs and CD8+ exhausted T cells promotes an immunosuppressive environment [9]. In head and neck squamous cell carcinoma, SPP1+ macrophages promote cancer progression by secreting TNF-α and IL-1β [10].

In conclusion, Spp1 plays diverse and significant roles in multiple disease conditions. Gene knockout and conditional knockout mouse models have been instrumental in revealing its functions in diseases such as NASH, fibrosis, Alzheimer's disease, and various cancers. Understanding Spp1's functions provides potential therapeutic targets for these diseases.