Yuning Hou, Chunlu Fang, Wenqi Yang, Shujing Liu, Liangming Li
Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein involved in cardiovascular protection, tissue repair, inflammation, fibrosis, and tumor biology. Accumulating evidence indicates that FSTL1 exerts opposing effects across tissues and disease contexts, producing either protective or pathogenic outcomes. Although this functional duality is generally considered context dependent, its mechanistic basis remains incompletely understood. Recent studies suggest that FSTL1 does not signal through a single receptor but engages or modulates multiple functionally distinct receptor systems, including disco-interacting protein 2 homolog A (DIP2A), Toll-like receptor 4/cluster of differentiation 14 (TLR4/CD14), and bone morphogenetic protein (BMP) receptors. DIP2A predominantly mediates cell survival and tissue repair, whereas TLR4/CD14 primarily coordinates innate immune and inflammatory responses. FSTL1 also modulates BMP ligand-receptor signaling, thereby influencing development, differentiation, tissue remodeling, and context-dependent tumor responses. The net biological output of FSTL1 is therefore proposed to be shaped by cell-type-specific receptor expression, post-translational modifications, microenvironmental cues, and potential crosstalk or competition among coexisting receptor systems. From a translational perspective, non-receptor-selective targeting of FSTL1 carries inherent risks because it may simultaneously suppress protective and pathological signaling programs. Receptor-selective approaches, including the development of DIP2A-biased agonists to enhance tissue protection and the selective disruption of pathological TLR4 signaling to attenuate inflammation, may offer greater therapeutic precision. This review proposes a receptor-centered framework for understanding the functional complexity of FSTL1 and discusses receptor-selective intervention strategies for cardiovascular, fibrotic, inflammatory, and malignant diseases.