IFN-γ could induce ferroptosis in keloid fibroblasts by inhibiting the expression of serpine2.

Keloids are common pathological scars resulting from previous trauma or inflammation. Interferon-gamma (IFN-γ) has shown significant therapeutic effects when used alone or in combination with other agents. While IFN-γ has been found to regulate ferroptosis in tumor cells, its ability to regulate ferroptosis in keloid fibroblasts (KFs) is unclear. Here, we have demonstrated a direct causal relationship between IFN-γ levels and ferroptosis in KFs. To explore the intrinsic mechanism, we performed genome-wide RNA and proteomics sequencing and found that serpine2 was the most significantly downregulated gene in KFs after exogenous overexpression of IFN-γ. Serpine2, which belongs to a family of serine protease inhibitors, has been shown to play an important role in fibrotic diseases. Therefore, we hypothesized that serpine2 is a downstream gene in the regulation of ferroptosis in KFs by IFN-γ. Our results showed that serpine2 overexpression promotes collagen synthesis, which in turn promotes the proliferation, migration, and invasive functions of KFs. We further demonstrated that serpine2 overexpression promoted system Xc transporter expression, cystine uptake, and glutathione synthesis, enhanced GPX4 activity; and inhibited reactive oxygen species generation. This resulted in a reduction in intracellular lipid peroxidation and the levels of its metabolite malondialdehyde, as well as inhibited ferroptosis in KFs. IFN-γ reversed these effects of serpine2 overexpression. These results were largely confirmed in in vivo keloid models too. These findings imply that IFN-γ not only directly induces ferroptosis in KFs but also enhances their sensitivity to ferroptosis by inhibiting the synthesis of SLC7A11 and SLC3A2 through downregulation of serpine2. In summary, we suggest that the serpine2-system Xc axis is a promising therapeutic target for the treatment of keloids.