TNFSF12

Tumor necrosis factor ligand superfamily member 12 (TNFSF12), also known as TWEAK (TNF-related weak inducer of apoptosis), is a type II transmembrane protein that can be proteolytically processed into a soluble cytokine. It binds to fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member, initiating downstream signaling through NF-κB and MAPK pathways. This interaction regulates diverse cellular processes including angiogenesis, pro-inflammatory responses, and tissue remodeling. TWEAK signaling plays critical roles in pathological conditions such as chronic inflammation, tumor progression, and neurodegenerative diseases through its dual functions in promoting cell survival under stress while triggering apoptosis in specific contexts.
Elevated TWEAK/Fn14 axis activity has been implicated in hepatocellular carcinoma, rheumatoid arthritis, and ischemic stroke. Therapeutic strategies targeting this pathway include anti-TWEAK monoclonal antibodies (e.g., BIIB023) and Fn14 decoy receptors, with several candidates demonstrating efficacy in preclinical models of solid tumors and autoimmune disorders. Small molecule inhibitors blocking TWEAK-induced NF-κB activation are under investigation for neurodegenerative conditions. Recent phase I trials have established favorable safety profiles for TWEAK-targeted biologics, though their therapeutic windows require further validation in disease-specific clinical settings.