Sulf2, also known as Sulfatase 2, is a member of the sulfatase family. It is an extracellular heparan sulfatase that removes 6-O sulfate residues from N-glucosamine on heparan sulfate (HS). The sulfation pattern of HS influences signaling events mediated by heparan sulfate proteoglycans (HSPGs) on the cell surface, which are crucial for interactions with growth factors and their receptors. Sulf2 is involved in multiple signaling pathways, such as TGFβ-SMAD signaling, and plays a role in various biological processes including cell differentiation, tumorigenesis, and immune regulation [2,3,4]. Genetic models, like genetically engineered murine models (GEMMs), have been valuable in studying Sulf2.

In pancreatic cancer, Sulf2 expression was increased at the acinar-to-ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC) stages. Sulf2 promoted the dedifferentiation of acinar cells and the metastatic ability of PDAC. It enhanced TGFβ-SMAD signaling via GDF15, and serum Sulf2 was elevated in PDAC patients, which could be combined with CA19-9 for better diagnosis [1]. In bladder cancer, high Sulf2 expression was associated with poor prognosis in high-grade patients and might be a novel diagnostic marker for those with lymphatic metastasis [2]. In cervical cancer, Sulf2 was upregulated, and its down-regulation inhibited the ERK1/2 and AKT signaling pathways, suppressing cell proliferation, invasion, and migration while facilitating apoptosis [3]. In prostate cancer, overexpression of Sulf2 increased cell viability, migration, and colony formation, suggesting a pro-tumorigenic effect [4]. In inflammatory arthritis, Sulf2 deficiency increased type I interferon signaling in macrophages, leading to elevated expression of the Th17-inducing cytokine IL6, indicating that Sulf2 limits type I interferon signaling in macrophages to protect against Th17-driven pathology [5].

In conclusion, Sulf2 is involved in various biological functions and disease processes. Through the use of gene-knockout or conditional-knockout mouse models and other functional studies, we have gained insights into its role in cancer development, immune regulation, and inflammatory diseases. These findings contribute to our understanding of disease mechanisms and may provide potential diagnostic and therapeutic targets for related diseases.