CILP2 (cartilage intermediate layer protein 2) is a secreted extracellular matrix component initially characterized in cartilage that has emerged as a pleiotropic modulator of metabolic and pathological processes 1. Primary function: CILP2 regulates glucose metabolism and insulin sensitivity, particularly in skeletal muscle, where elevated expression impairs myogenic differentiation and glucose uptake 2. Mechanism: CILP2 suppresses the Wnt/β-catenin signaling pathway through interaction with Wnt3a, reducing myogenesis and mitochondrial function 2. It also stabilizes ATP citrate lyase (ACLY) to promote fibroblast activation and collagen synthesis 3, and activates PPARγ signaling to increase lipid uptake via CD36 upregulation 4. Disease relevance: CILP2 is upregulated in sarcopenia, dyslipidemia, coronary heart disease, hypertrophic scars, and multiple cancers 1. Genetic variants at the NCAN-CILP2 locus associate with cardiovascular risk factors and lipid profiles 56. CILP2 knockdown in aged mice improved muscle mass, grip strength, and glucose metabolism 2. Clinical significance: Circulating CILP2 levels correlate with disease severity and poor prognosis across multiple conditions 7, making it a promising biomarker and therapeutic target for metabolic and fibrotic diseases.