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), influencing signaling events mediated by heparan sulfate proteoglycans (HSPGs) on the cell surface, which are crucial for interactions with growth factors and their receptors [3]. It is involved in various signaling pathways such as TGFβ -SMAD, ERK/AKT, and WNT, and plays important roles in biological processes related to cancer, inflammation, and vascular regeneration. Genetically engineered murine models (GEMMs) have been valuable for studying Sulf2.

In pancreatic cancer, multiple GEMMs verified that Sulf2 expression increased at the acinar -to -ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC) stages. Sulf2 promoted acinar cell dedifferentiation and PDAC metastatic ability, enhanced TGFβ -SMAD signaling via GDF15, and serum Sulf2 was elevated in PDAC patients, improving diagnosis when combined with CA19 -9 [1].

In cervical cancer, down -regulation of Sulf2 in HeLa cells inhibited the ERK1/2 and AKT signaling pathways, suppressing cell proliferation, invasion, and migration while promoting apoptosis. A xenograft model in nude mice confirmed the in -vivo role of Sulf2 in promoting tumor growth [2].

In prostate cancer cell lines, over -expression of Sulf2 increased cell viability, migration, and colony formation, and there were changes in HS structure, epithelial -mesenchymal transition markers, and the WNT signaling pathway [3].

In inflammatory arthritis, Sulf2 -deficient myeloid bone marrow chimeric mice had impaired inflammation resolution, elevated joint swelling, and increased pro -arthritic Th17 cells, as Sulf2 deficiency increased type I interferon signaling in macrophages [4].

In conclusion, Sulf2 plays significant roles in cancer initiation, progression, and metastasis, as well as in inflammatory processes. The use of gene knockout (KO) or conditional knockout (CKO) mouse models, such as those in pancreatic cancer, cervical cancer, prostate cancer, and inflammatory arthritis studies, has been crucial in revealing these functions. Understanding Sulf2's functions can potentially provide new diagnostic and prognostic markers, as well as therapeutic targets for related diseases.