IL6ST (interleukin 6 cytokine family signal transducer), also known as gp130, encodes a shared signal-transducing subunit for nine human cytokine receptor complexes including IL-6, IL-11, IL-27, and others 1. IL6ST functions as a coreceptor that binds soluble IL-6 receptor (sIL6R) complexes and blocks IL-6 trans-signaling and sIL6R-dependent acute phase responses 2. It mediates downstream JAK/STAT signaling pathways essential for immune homeostasis and inflammatory responses 3. IL6ST undergoes chaperone-mediated autophagy (CMA) degradation; impaired CMA-dependent degradation promotes hepatocellular carcinoma cell proliferation and migration, suggesting a tumor-suppressor role 4. Loss-of-function variants in IL6ST cause autosomal dominant or recessive hyper-IgE syndrome (HIES) and immunodeficiency through dominant-negative effects, where truncated proteins accumulate on the cell surface and impair signaling geometry 5 6. Disease-associated IL6ST variants alter transmembrane helix geometry and increase extracellular domain flexibility, disrupting the stringent structural requirements for effective cytokine signaling 6. Pharmacological modulation of IL6ST signaling via agents like SC144 shows therapeutic potential in cancer and inflammatory diseases 7.