CLCF1 is a member of the IL-6 cytokine superfamily that forms a heterodimeric complex with CRLF1 to function as a neurotropic cytokine 1. It binds to and activates gp130 receptors, triggering intracellular signaling cascades through JAK-STAT and ERK1/2 pathways 23. During development, CLCF1 plays crucial roles in neuronal development and supports B cell proliferation and differentiation 41. In adults, circulating CLCF1 levels decrease with age but are upregulated by exercise; restoring CLCF1 improves physical performance, glucose tolerance, mitochondrial activity, and protects against age-related bone loss by inhibiting osteoclastogenesis 5. CLCF1 also regulates thermogenesis and is inversely regulated by thyroid hormones 6. Pathologically, CLCF1 dysfunction causes Crisponi/cold-induced sweating syndrome-2, a severe neonatal disorder 7. In cancer, CAF-derived CLCF1 promotes hepatocellular carcinoma progression through a positive feedback loop involving CXCL6 and TGF-β, enhancing tumor stemness and immune infiltration 2. CLCF1 represents an emerging therapeutic target for age-related musculoskeletal decline, metabolic disorders, and cancer.