Mechanistic interrogation of mutation-independent disease modulators of RDEB identifies the small leucine-rich proteoglycan PRELP as a TGF-β antagonist and inhibitor of fibrosis

•Severe fibrotic features in recessive dystrophic epidermolysis bullosa (RDEB) are favored by a pro-oxidant status and hyper-responsiveness to TGF-β of dermal fibroblasts.•Antioxidant treatment reducing intrinsic high levels of ROS reverses part of the pro-fibrotic and contractile phenotype.•Prolargin / PRELP arises as a novel regulator of skin homeostasis by reducing TGF-β-driven fibrotic cues and promoting dermo-epidermal adherence.