TWEAK/Fn14 axis: The current paradigm of tissue injury-inducible function in the midst of complexities

• The TWEAK/Fn14 pathway has emerged as a prominent, injury-induced molecular axis.
• Fn14 signaling potentials are complex; depend on nature and degree of Fn14 engagement.
• Chronic activation promotes a dysregulated wound healing response.
• Drives pathological tissue changes in settings of chronic injury and fibrosis.
• Regulates malignancy with protumoral and anti-tumoral effects.

TNF-like weak inducer of apoptosis (TWEAK), a TNF family ligand, and its only known signaling receptor, FGF-inducible molecule-14 (Fn14), have emerged as a key molecular pathway regulating tissue responses after acute tissue injury and in contexts of chronic injury and disease, including autoimmunity, chronic inflammation, fibrosis, and malignancy. Usually dormant due to the low level of Fn14 expression in healthy tissues, this axis is specifically activated by the upregulation of Fn14 expression locally within injured tissues, thereby triggering a wide range of activities in tissue parenchymal and stromal cells as well as tissue progenitor cells. Current evidence supports that although transient TWEAK/Fn14 pathway activation may be beneficial for tissue repair after acute injury, excessive or sustained TWEAK/Fn14 activation due to repeated injury or chronic disease mediates significant tissue damage and pathological tissue remodeling. This paradigm for the dichotomous function of the TWEAK/Fn14 pathway is discussed, highlighting emerging findings, complexities, and implications for the treatment of tissue damage-associated pathologies and cancer.