IL-6 is a pleiotropic cytokine that plays dual roles in liver regeneration, aging, inflammation, and disease. It exerts anti-inflammatory effects by promoting hepatocyte reprogramming and liver regeneration, but also pro-inflammatory effects that contribute to liver aging, fibrosis, steatosis, and carcinogenesis. IL-6 signaling occurs through three modes: cis-, trans-, and cluster signaling. The trans-signaling pathway is particularly important for liver regeneration, as it involves the interaction of IL-6 with soluble IL-6R (sIL-6R) and subsequent activation of gp130. IL-6 also activates multiple signaling pathways, including JAK-STAT, MAPK, PI3K, and YAP, which regulate gene expression and cellular processes. In liver regeneration, IL-6 promotes hepatocyte proliferation and liver regeneration, but excessive IL-6 can lead to liver damage and disease. In liver aging, IL-6 is produced by senescent cells and contributes to chronic liver diseases. IL-6 also plays a role in liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). Therapeutic strategies targeting IL-6 signaling, including antibodies and small molecules, have shown promise in treating inflammatory diseases and cancers. However, global inhibition of IL-6 signaling can have adverse effects, and selective inhibition of IL-6 trans-signaling is more effective and safer. IL-6 is a double-edged sword, with both beneficial and harmful effects depending on the context. Understanding the roles of IL-6 in liver physiology and pathology is crucial for developing targeted therapies.IL-6 is a pleiotropic cytokine that plays dual roles in liver regeneration, aging, inflammation, and disease. It exerts anti-inflammatory effects by promoting hepatocyte reprogramming and liver regeneration, but also pro-inflammatory effects that contribute to liver aging, fibrosis, steatosis, and carcinogenesis. IL-6 signaling occurs through three modes: cis-, trans-, and cluster signaling. The trans-signaling pathway is particularly important for liver regeneration, as it involves the interaction of IL-6 with soluble IL-6R (sIL-6R) and subsequent activation of gp130. IL-6 also activates multiple signaling pathways, including JAK-STAT, MAPK, PI3K, and YAP, which regulate gene expression and cellular processes. In liver regeneration, IL-6 promotes hepatocyte proliferation and liver regeneration, but excessive IL-6 can lead to liver damage and disease. In liver aging, IL-6 is produced by senescent cells and contributes to chronic liver diseases. IL-6 also plays a role in liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). Therapeutic strategies targeting IL-6 signaling, including antibodies and small molecules, have shown promise in treating inflammatory diseases and cancers. However, global inhibition of IL-6 signaling can have adverse effects, and selective inhibition of IL-6 trans-signaling is more effective and safer. IL-6 is a double-edged sword, with both beneficial and harmful effects depending on the context. Understanding the roles of IL-6 in liver physiology and pathology is crucial for developing targeted therapies.