HHIP (hedgehog interacting protein) is a negative regulator of hedgehog signaling that modulates the Hh/GLI pathway across multiple tissues, particularly in lung and brain 1. As a key component of the hedgehog signaling cascade, HHIP functions alongside other repressive regulators to inhibit smoothened signaling and prevent GLI transcription factor activation 1. In lung development and homeostasis, HHIP plays critical roles in alveologenesis and epithelial-mesenchymal interactions. During alveolar formation, HHIP-expressing stromal cells inhibit hedgehog signaling, preventing myofibroblast accumulation and allowing proper epithelial stem cell expansion 2. HHIP dysregulation contributes significantly to chr4 lung disease pathogenesis. Reduced HHIP expression in airway epithelial cells from COPD patients impairs cigarette smoke-induced epithelial repair and promotes epithelial-to-mesenchymal transition 3. Loss of stromal HHIP expression in emphysema activates a hyperactive hedgehog-IL-7 axis that expands tissue-resident lymphocytes, which subsequently suppress alveolar stem cell growth through interferon-gamma signaling 4. Early HHIP deficiency leads to bronchopulmonary dysplasia and adult emphysema with persistent myofibroblast accumulation 2. Beyond lung disease, HHIP expression is significantly downregulated in liver cancer, and HHIP overexpression inhibits hepatocellular carcinoma cell growth, migration, and invasion 5. Therapeutic HHIP administration mitigates bronchopulmonary dysplasia and prevents emphysema development, establishing HHIP as a potential therapeutic target 2.