ADAM17 as a proteolytic rheostat linking inflammation, tissue repair, and failure of inflammatory resolution in liver injury and fibrosis

A disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound sheddase that regulates inflammatory signaling, tissue repair, and fibrotic remodeling by converting cell-surface proteins into soluble forms. Rather than viewing ADAM17 simply as a proinflammatory enzyme, this review frames it as a proteolytic rheostat that dynamically adjusts the balance between membrane-bound and soluble molecular states in the injured liver. Within this framework, apparently opposing effects of ADAM17 can be understood as substrate-, cell-, and disease-stage-dependent consequences of ectodomain shedding. We particularly highlight two independently observed patterns of macrophage receptor-state remodeling: insufficient MerTK shedding may preserve profibrotic MerTK/ERK/TGF-β1 signaling, whereas excessive TREM2 shedding may reduce efferocytic capacity and contribute to failed inflammatory resolution. We further discuss how ADAM17-mediated shedding reshapes hepatocyte–macrophage–HSC communication and how soluble shedding products may provide circulating readouts of these processes. This framework suggests that therapeutic strategies should move beyond broad ADAM17 inhibition toward context-, cell-, or substrate-selective modulation that limits pathogenic signaling while preserving inflammation-resolving and tissue-repair functions.