New Review Highlights TWEAK/Fn14 Pathway's Potential

A new review published in International Immunopharmacology explores the expanding role of the TWEAK/Fn14 signaling pathway in both skin disease pathogenesis and stem cell regulation, proposing its potential as a dual-purpose therapeutic and diagnostic target in dermatology and regenerative medicine.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) interacts with fibroblast growth factor-inducible 14 (Fn14) to regulate critical biological functions including proliferation, inflammation, angiogenesis, and apoptosis. In skin diseases such as psoriasis, systemic lupus erythematosus (SLE), and cutaneous malignancies, aberrant activation of the TWEAK/Fn14 pathway contributes to inflammation, fibrosis, and chronic tissue damage. Conversely, moderate activation supports wound healing and tissue regeneration.

The authors detail the pathway’s role in regulating various stem cell populations, including hepatic, neural, muscle, and mesenchymal stem cells. TWEAK/Fn14 modulates their proliferation, differentiation, and migration, promoting regeneration but potentially contributing to pathological remodeling if overactivated. For example, in psoriasis, the pathway enhances keratinocyte proliferation and cytokine production, while in SLE, elevated serum and urinary TWEAK levels correlate with disease activity and renal involvement, suggesting biomarker utility.

Therapeutic strategies targeting this pathway are under investigation. Anti-TWEAK antibodies, Fn14-Fc fusion proteins, and small molecule inhibitors have demonstrated efficacy in preclinical models of SLE and chronic inflammation. In contrast, activating TWEAK/Fn14 signaling has shown benefits in wound healing applications, such as burn repair.

“The ability of the TWEAK/Fn14 pathway to simultaneously modulate inflammation and regeneration highlights its therapeutic potential,” the authors wrote. “A deeper understanding of this signaling axis could inform more targeted treatments for inflammatory skin diseases and regenerative applications.”¹