Sulf1, also known as Sulfatase 1, is an enzyme that modifies heparan sulfate chains of heparan sulfate proteoglycans (HSPGs) [1,2,3,5,6,7,9,10]. By desulfating HSPGs, it can modulate the binding of numerous signaling molecules, thereby affecting many physiological and pathological processes [5]. It is involved in pathways like TGF-β1/SMAD, FAK/PI3K/AKT/mTOR, VEGFR2/PI3K/AKT, and Wnt signaling, playing a crucial role in biological regulation [1,2,5,6,8].

In idiopathic pulmonary fibrosis, Sulf1 is upregulated in lung tissues of patients, and its knockdown in HFL1 cells suppresses fibroblast functions like secretion, activation, proliferation, migration, and invasion, suggesting it promotes fibrosis through the TGF-β1/SMAD pathway [1]. In colorectal cancer, knockdown of Sulf1 inhibits cell proliferation, invasion, and migration, while increasing apoptosis, indicating its role in promoting CRC progression via the FAK/PI3K/AKT/mTOR pathway by regulating ARSH [2]. In cervical cancer, Sulf1 promotes tumorigenesis and development by activating the VEGFR2/PI3K/AKT pathway [5]. In the context of bone metastatic prostate cancer, Sulf1 produced by bone marrow fibroblasts suppresses Wnt3A-driven growth in the desmoplastic stroma, and its loss favors cancer progression [4]. In gastric cancer, cancer-associated fibroblasts-derived Sulf1 promotes metastasis and CDDP resistance through the TGFBR3-mediated TGF-β signaling pathway [9]. In colorectal cancer, Sulf1+ cancer-associated fibroblasts enhance VEGFA release, promoting extracellular matrix deposition and angiogenesis [10].

In summary, Sulf1 is an important enzyme that modulates multiple signaling pathways. Through loss-of-function experiments in various cell lines and in some cases, by implication in disease-relevant models, it has been shown to play significant roles in fibrosis and multiple types of cancer, highlighting its potential as a therapeutic target in these disease areas.