TWEAK-Fn14: a promising target for cardio-cerebrovascular diseases and brain-heart syndrome

Cardio-cerebrovascular diseases (CCVDs), notably stroke and coronary heart disease, represent the leading causes of mortality and disability worldwide. The intricate bidirectional feedback between the brain and heart in brain-heart syndrome (BHS) exacerbates clinical outcomes and imposes a significant economic burden on patients. The cytokine tumor necrosis factor-like apoptosis weak inducer (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are overexpressed in cerebral injury and cardiac dysfunction. Elevated levels of TWEAK and Fn14 contribute to the development of various brain diseases, including blood-brain barrier damage, brain edema, neuroinflammation, neuronal apoptosis, and neurodegeneration. Additionally, the TWEAK-Fn14 axis is implicated in numerous pathophysiological events in the heart, such as cardiomyocyte proliferation, inflammation, apoptosis, hypertrophy, fibrosis, contractile function disruption, and ventricular dilatation. Given its significant contributions to CCVDs, the TWEAK-Fn14 axis has also emerged as a promising therapeutic target for BHS. In this review, the critical roles of TWEAK-Fn14 in CCVDs and its potential interplay between the brain-heart axis in BHS were updated and discussed, which shed a new light on co-treatment of brain and heart and brain-heart syndrome.