Interleukin-6 (IL-6) is a pleiotropic cytokine that exerts complex biological functions through three signal modes: cis-, trans-, and cluster signaling. IL-6 plays a dual role in liver homeostasis, aging, inflammation, and chronic diseases. In the liver, IL-6 promotes hepatocyte reprogramming and regeneration by activating the gp130 co-receptor, but it also induces liver aging, fibrosis, steatosis, and carcinogenesis. The effector signaling of IL-6 involves the activation of downstream pathways such as JAK-STAT, MAPK, PI3K, and YAP, leading to the transcription of target genes. IL-6 trans-signaling, involving the interaction between IL-6 and soluble IL-6R (sIL-6R), is particularly important for liver regeneration and is more effective than classic signaling. IL-6 also has anti-inflammatory effects, which can ameliorate liver injury and fibrosis. However, high levels of IL-6 in aged livers promote inflammation and chronic liver diseases. Therapeutic strategies targeting IL-6 signaling, including neutralizing antibodies and small molecules, have shown promise in treating inflammatory diseases, metabolic disorders, and cancers. Selective inhibition of IL-6 trans-signaling, rather than global blockade, may be more effective in treating liver pathologies. Understanding the precise mechanisms and timing of IL-6 action is crucial for developing targeted therapies.Interleukin-6 (IL-6) is a pleiotropic cytokine that exerts complex biological functions through three signal modes: cis-, trans-, and cluster signaling. IL-6 plays a dual role in liver homeostasis, aging, inflammation, and chronic diseases. In the liver, IL-6 promotes hepatocyte reprogramming and regeneration by activating the gp130 co-receptor, but it also induces liver aging, fibrosis, steatosis, and carcinogenesis. The effector signaling of IL-6 involves the activation of downstream pathways such as JAK-STAT, MAPK, PI3K, and YAP, leading to the transcription of target genes. IL-6 trans-signaling, involving the interaction between IL-6 and soluble IL-6R (sIL-6R), is particularly important for liver regeneration and is more effective than classic signaling. IL-6 also has anti-inflammatory effects, which can ameliorate liver injury and fibrosis. However, high levels of IL-6 in aged livers promote inflammation and chronic liver diseases. Therapeutic strategies targeting IL-6 signaling, including neutralizing antibodies and small molecules, have shown promise in treating inflammatory diseases, metabolic disorders, and cancers. Selective inhibition of IL-6 trans-signaling, rather than global blockade, may be more effective in treating liver pathologies. Understanding the precise mechanisms and timing of IL-6 action is crucial for developing targeted therapies.