Updated project metadata. We performed comprehensive proteome profiling (ECM and cell lysate) of human collagen VII deficient and control epidermal keratinocytes to generate global and detailed images of dysregulated epidermal molecular pathways linked to loss of collagen VII. These revealed downregulation of interaction partners of collagen VII, but also increased abundance of S100 pro-inflammatory proteins and enhanced activity of lysosomal proteases. Thus, loss of a single extracellular structural protein, collagen VII, induced persistent fibrosis enabling inflammatory and tissue destabilizing activities of keratinocytes.