An update on TWEAK/Fn14 signaling pathway: A comprehensive review

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional protein, present in various cell types and tissues, which, upon binding to the receptor factor-inducible 14 (Fn14), is involved in diverse pathologic processes including cell proliferation and death, angiogenesis, carcinogenesis, and inflammation. Interestingly, any alterations of their intracellular signaling are well correlated with the advancement of several diseases. The expression of TWEAK and Fn14 is augmented in many solid tumors compared with healthy tissues, thus leading to the enhancement of the proliferation, invasion, and subsequent migration of tumor cells. However, few TWEAK/Fn14 targeting pharmacological agents involved in inhibiting the progression of tumors have shown initial success in both clinical and pre-clinical experimental settings. Moreover, such agents improved angiogenesis, pro-inflammatory cytokine expression, and epithelial–mesenchymal transitions, upon TWEAK/Fn14 activation. This review provides an overview of the current understanding of the TWEAK–Fn14 signaling axis, its role in augmenting pathological characteristics of various diseases, and the existence of potential therapeutic targets for the development of novel pharmacological interventions.