Alternative splicing generates a constitutively active Fn14 isoform that signals independently of TWEAK

However, clinical strategies aimed at blocking its activation by preventing engagement with its ligand TNF-like weak inducer of apoptosis (TWEAK) have demonstrated limited efficacy, suggesting alternative mechanisms of Fn14 activation. Here, we identified Fn14β, a novel Fn14 isoform, encoded by the alternatively spliced transcript TNFRSF12A-202.

Transcriptomic analyses showed that TNFRSF12A-202 is expressed across human tissues and liver disease contexts, localises to fibrotic regions in vivo, and is associated with reduced overall survival in hepatocellular carcinoma. Structural modelling predicted that Fn14β lacks the extracellular TWEAK-binding domain while retaining the intracellular TRAF-binding signalling domain. CRISPR/Cas9-mediated selective ablation of the canonical Fn14 isoform demonstrated that endogenous Fn14β is expressed and sufficient to drive downstream transcriptional programmes shared with canonical Fn14a.