NEURL1-mediated K63-ubiquitination of SLC40A1 drives ferroptosis resistance in pathological scars: Therapeutic targeting via autophagy-activating microneedles

Abstract

Ferroptosis resistance contributes to pathological skin scarring, but the underlying regulatory mechanisms remain unclear. Here, we identified a novel selective autophagy pathway NEURL1-SQSTM1/p62-SLC40A1 that controls fibroblast ferroptosis and scar formation. SLC40A1 is upregulated in human scars, conferring ferroptosis resistance by promoting iron efflux. Mechanistically, NEURL1 mediates K63-linked ubiquitination of SLC40A1, enabling its recognition by SQSTM1 for lysosomal degradation. A microneedle system co-delivering curcumin (autophagy activator) and siSLC40A1 effectively activates this axis, induces ferroptosis, and alleviates scarring in vivo. Our findings reveal a new therapeutic target and strategy for pathological scars.