As the converging point of numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) play a central role in regulating antitumor immune responses. STAT3 is extensively overactivated in both cancerous and non-cancerous cells within the tumor ecosystem and plays a vital role in suppressing the expression of key immune activation regulators and promoting the production of immunosuppressive factors. Mutations in human STAT3 are associated with diseases such as immunodeficiency, autoimmunity, and cancer. In recent years, many studies have shown that STAT3 is closely related to the occurrence and development of liver fibrosis caused by various factors. Activation of STAT3 may play an anti- or pro-inflammatory role in the pathogenesis of liver fibrosis. Furthermore, mitochondrial translocation of STAT3 inhibits oxidative stress-induced autophagy and may effectively protect mitochondria from degradation by mitophagy. Strikingly, however, either overactivation or inactivation of STAT3 leads to human disease, suggesting that tightly regulated STAT3 function is critical for health. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for many cancers.
Interleukin-23 (IL-23) is a heterodimeric cytokine belonging to the IL-6/IL-12 family that plays a key role in several of autoimmune and inflammatory disorders. This family contains the 34 type I cytokine receptor chains and 27 ligands, which share structural and functional similarities, but on the other hand they display distinct roles in shaping Th cells responses. IL-12 family cytokines have not only proinflammatory effects but they also promote inflammatory responses. IL-23 is composed of the p40 subunit in common with IL-12, and with a unique p19 subunit. IL-23 binding to an IL-23 receptor expressed on dendritic cells, macrophages and monocytes triggers the activation of Jak2 and Tyk2, which in turn phosphorylates STAT1, STAT3, STAT4 and STAT5 as well as induce formation of STAT3-STAT4 heterodimers. IL-23 is one of the essential factors required for the survival and/or expansion of Th17 cells, which produce IL-17, IL-17F, IL-6 and TNF-α. Th17 cells stimulated by the IL-23 promote osteoclastogenesis through production of IL-17, which induce receptor activator of NF-kappa B ligand on mesenchymal cells. The IL-23-IL-17 axis includes Th17 cells and plays a key role in the development of autoimmune arthritis.
