Tumor necrosis factor-like weak inducer of apoptosis–Fibroblast growth factor-inducible 14 complex (TWEAK–FN14)

The TWEAK–FN14 ligand–receptor interface is a signaling axis composed of the Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK) ligand and its highly inducible receptor, Fibroblast Growth Factor-inducible 14 (FN14) (Winkles, 2008, PMID: 18448455). While TWEAK is a member of the TNF superfamily (TNFSF12), FN14 is its sole known signaling receptor (TNFRSF12A) and is characterized by its small size and lack of a death domain (Burkly et al., 2011, PMID: 21441922). Under normal physiological conditions, FN14 expression is minimal but increases significantly in response to tissue injury, where it coordinates repair processes such as angiogenesis and progenitor cell proliferation (Cheng et al., 2013, PMID: 23543134). However, persistent activation of this interface is linked to various pathologies, including chronic inflammation, fibrosis, and the progression of solid tumors (Burkly, 2014, PMID: 25309543). In cancer, the TWEAK–FN14 axis promotes tumor cell survival, migration, and invasion by activating the NF-κB and MAPK signaling pathways (Culp et al., 2010, PMID: 20068083). Therapeutic targeting of this interface has focused on monoclonal antibodies that either neutralize the TWEAK ligand or block the FN14 receptor to prevent complex formation. Despite promising preclinical data, clinical development has faced challenges regarding efficacy and potential side effects like hepatotoxicity (ClinicalTrials.gov, NCT00876616).

Other names

TNFSF12–TNFRSF12ATWEAK–TWEAKRTWEAK–CD266TWEAK–Fn14 axisTWEAK–Fn14 pathway

Inhibition of the TWEAK–FN14 interaction via monoclonal antibodies to block downstream NF-κB and MAPK signaling pathways.