The SMAD signaling pathway is regulated by various ligands, with members of the TGF-β family playing a significant role in modulating SMAD signaling and regulating skeletal muscle generation and metabolism.428 In cachexia patients, TGF-β family members (such as MSTN, TGF-β, and GDF15) bind to receptor complexes (TGFβRI, TGFβRII, and ActRIIB), leading to the phosphorylation of Smad2 and Smad3, which then combine with Smad4. The gene discussed is GDF15; the disease is Cachexia.