CREG1 (cellular repressor of E1A-stimulated genes 1) is a secreted endolysosomal glycoprotein that regulates cell differentiation and homeostasis through multiple mechanisms. Mechanistically, CREG1 promotes autophagy and mitophagy by enhancing lysosomal biogenesis and function 1, and signals through the IGF2R-PI3K-AKT pathway to regulate osteogenic and myogenic differentiation 2. CREG1 protects against C-Cbl-mediated degradation of AMPKα1, a key regulator of muscle regeneration 3. Clinically, CREG1 demonstrates broad tissue-protective functions. In skeletal muscle, CREG1 deficiency impairs myoblast differentiation and regeneration following injury 3. In bone, CREG1 overexpression alleviates osteoporosis by enhancing osteogenic differentiation of bone marrow mesenchymal stem cells through mitophagy 4. CREG1 regulates megakaryocyte maturation and thrombopoiesis through MEK1/2 phosphorylation, with deficiency causing thrombocytopenia 5. In intervertebral discs, CREG1 attenuates degeneration by suppressing NLRP3-mediated pyroptosis via PINK1/Parkin-dependent mitophagy 6. Hepatocyte CREG1 protects against acetaminophen-induced liver injury and alcohol-induced liver disease by promoting autophagy and inhibiting stress kinase pathways 78. In cardiac tissue, CREG1 loss causes progressive hypertrophy, fibrosis, and diastolic dysfunction with increased nutritional stress susceptibility 1. These findings establish CREG1 as a promising therapeutic target across multiple degenerative diseases.