VEGF-B: A multifaceted modulator with emerging therapeutic applications.

Long overshadowed by VEGF-A, vascular endothelial growth factor B (VEGF-B) has emerged as a critical regulator of vascular, metabolic, and immune cross-talk. Unlike the potent angiogenic factor VEGF-A, VEGF-B does not induce vascular leakage but modulates tissue-specific functions, including fatty acid transport, neuronal survival, and immunometabolism, through its receptors VEGFR1 and NRP1. Its roles are often paradoxical, suppressing angiogenesis in some cancers while promoting metastasis and immune evasion in others, highlighting its profoundly context-dependent nature of action. Recent discoveries, such as the identification of FGFR1 as a key receptor and the essential role of VEGF-B in T cell survival, have revitalized interest in its therapeutic potential. However, clinical translation remains challenging, as exemplified by the recent failure of the anti-VEGF-B antibody CSL346 in diabetic kidney disease, underscoring our incomplete understanding of VEGF-B biology. This review integrates cutting-edge insights into the diverse functions of VEGF-B, proposes a mechanistic framework for its complex signaling networks, and outlines a roadmap for developing precision therapies for metabolic, cardiovascular, neurodegenerative, and oncological diseases. We address the critical translational challenges to maximize the therapeutic benefits while preserving the crucial homeostatic functions of VEGF-B.