Figure 3. (A) A model of the senescence-inducing circuit involving the IL-6-STAT3-IGFBP5 axis. IGFBP5 produced in a STAT3-dependent manner causes the initial generation of ROS, subsequent DDR and SASP (expression of IL-1α, IL-1β, IL-6, and CXCL8). Prolonged expression of IGFBP5 caused by IL-6, together with other components of SASP, drives the circuit generating more ROS and severe DNA damage, leading to p53-dependent premature senescence. Inhibition of any constituent, STAT3, p53, ROS, IGFBP5, or RelA attenuates the IL-6/sIL-6Rα-induced premature senescence. The possible roles of the ERK1/2 and PI3K/AKT/mTOR-mediated pathways are discussed in the text. (B) The multiple roles of IL-6/STAT3 pathway. IL-6/STAT3 regulates multiple processes ranging from premature senescence to tumorigenesis.