Slc7a11/xCT mediated ferroptosis repression in dermal fibroblasts promotes cutaneous fibrosis

Here we demonstrate that the Slc7a11/xCT pathway, which represses iron-dependent cell death (ferroptosis) by preventing reactive oxygen species-mediated lipid peroxidation, is upregulated in dermal fibroblasts in SSc patients and in a mouse model of oxidative stress-induced skin fibrosis. We observe that deficiency or inhibition of Slc7a11 prevents fibrosis and collagen accumulation. We further show that SSc dermal fibroblasts counteract ferroptosis by reducing the intracellular Fe2+ pool through enhanced ferritin storage thereby reducing lipid ROS sensitivity and lipid peroxidation. In line, SSc patients had low plasma iron levels and transferrin saturation rates and their fibroblasts contained less labile Fe2+ and showed less lipid peroxidation compared to healthy fibroblasts.