ISM1 (isthmin 1) is a secreted protein with diverse physiological roles extending beyond its canonical anti-angiogenic function. In the lung, ISM1 functions as a critical anti-inflammatory mediator that maintains homeostasis by selectively inducing apoptosis of pro-inflammatory alveolar macrophages expressing high levels of cell-surface GRP78 1. ISM1 deficiency leads to spontaneous emphysema and COPD-like pathology, while recombinant ISM1 delivery suppresses lipopolysaccharide-induced acute lung injury and post-injury fibrosis through NF-κB inhibition 2. In allergic asthma, ISM1 attenuates airway inflammation by stimulating adiponectin expression and promoting alveolar macrophage efferocytosis 3. Beyond pulmonary function, ISM1 protects against cardiac ischemia/reperfusion injury via the cGMP-PKG signaling pathway 4 and regulates glucose and lipid metabolism independent of insulin 5. However, ISM1 displays context-dependent oncogenic properties in colorectal cancer, where it enhances proliferation and metastasis through EGFR activation and YBX1-mediated transcriptional regulation 6. In white adipose tissue, ISM1 derived from stem/progenitor cells impairs adipocyte differentiation and amplifies inflammatory responses 7. ISM1 secretion is regulated by C-mannosylation in its thrombospondin type 1 repeat domain 8. These findings establish ISM1 as a multifunctional protein with significant therapeutic potential in respiratory and cardiac diseases, though its role in cancer requires careful consideration.