Sulfatase-mediated peroxidase-like activity: A chemiluminescence-based platform for high-throughput screening of natural inhibitors in cancer therapy

Sulfatase, traditionally known for its role in sulfate ester hydrolysis, has recently emerged as a potential player in tumor biology through its involvement in oxidative stress pathways. Here, we demonstrate for the first time that sulfatase exhibits peroxidase-like activity, catalyzing the generation of singlet oxygen (¹O₂) in the presence of oxygen. Based on the sulfatase-dependent ¹O₂ generation, the developed adamantly-enolether chemiluminescence probe QM-CF for imaging tumors of high sulfatase expression further verified the theory that sulfatase can be involved in tumor development. High-throughput screening (HTS) of natural compounds and clinical drugs identified scutellarin and sinomenine as potent sulfatase inhibitors that suppress tumor growth in mice. Mechanistic investigations revealed that these inhibitors modulate oxidative stress by downregulating MAPK and NF-κB pathways. Our findings unveil a previously unappreciated role of sulfatase in tumor-related oxidative stress and provide a promising platform for the discovery of novel sulfatase inhibitors, and advancing cancer therapeutics.