IFN? regulates ferroptosis in KFs by inhibiting the expression of SPOCD1 through DNMT3A
Keloid is benign skin tumor, and their curing is relatively difficult due to the unclear mechanism of formation. Inducing ferroptosis of keloid fibroblasts (KFs) may become a new method for treating keloid. Here, we discover interferon (IFN)? could induce KFs ferroptosis through inhibiting SPOC domain-containing protein 1 (SPOCD1), serving as a mode of action for CD8+T cell (CTL)-mediated keloid killing. Mechanistically, keloid IFN? deficiency in combination with reduced DNMT3A increase the expression of SPOCD1, thereby promoting KFs' proliferation and inhibiting its ferroptosis. Moreover, keloid SPOCD1 deficiency attenuates KFs progression and extracellular matrix (ECM) deposition. Reducing IFN? and SPOCD1 simultaneously can increase the positive rate of reactive oxygen species (ROS) and promote mitochondrial shrinkage. Ex-vivo explant keloid culture has also confirmed that the reduction of SPOCD1 helps to reduce the proliferation rate of KFs, inhibit the angiogenesis of keloid scars, and thus inhibit keloid formation. Thus, IFN? signaling paired with SPOCD1 is a natural keloid ferroptosis promoting mechanism and a mode of action of CTLs. Targeting SPOCD1 pathway is a potential anti-keloid approach. Overall design: In order to find the way to cure keloid, we apply RNA sequences to explore the different expression of gene in keloid. And we found the expression of SPOCD1is high in keloid. So, we hypothesis its important role in KFs' ferroptosis and verified the regulatory effect of IFN? on it.