TNFRSF12A/TWEAK

TNFRSF12A/Fn14 is a small TNF receptor superfamily member and the cell-surface receptor for TWEAK/TNFSF12, linking ligand binding to angiogenesis, endothelial proliferation, inflammation, and tissue-repair responses^[1][2]. Mechanistically, TWEAK-Fn14 activates canonical and non-canonical NF-κB signaling, with documented roles in myoblast proliferation, inhibited myogenesis, myoblast fusion, and skeletal muscle homeostasis^[3]. In disease models, Fn14 expression increases in kidney injury and correlates with histological disease severity, while TWEAK/Fn14 signaling contributes to muscle atrophy, cerebral ischemia, kidney injury, atherosclerosis, infarction, and autoimmune disease contexts^[4][5]. Compared with the full-length membrane receptor, soluble Fn14 has been detected in urine and serum in kidney disease models, and a Fn14 splice-variant deletion mutant can signal through NF-κB despite lacking TWEAK binding^[4][6]. For experimental applications, TWEAK-blocking strategies, Fn14-targeting biologicals, immunotoxins, and antibody-drug conjugates provide tools to inhibit TWEAK/Fn14 signaling or selectively target Fn14-expressing tumor cells^[5][7][8].