Stress-induced premature senescence (SIPS) is characterized by the secretion of a variety of inflammatory cytokines, chemokines, and proteases, which are defined collectively as the senescence-associated secretory phenotype (SASP). AMP-activated protein kinase (AMPK) activation contributes to SIPS prevention, and the impact of AMPK on SASP may be included, but the mechanisms governing this phenomenon have not elucidated. In this study, we showed that SIPS is accompanied by a dynamic fluctuation of NF-κB activation, which induces SASP production, whilst reinforcing and amplifying local STAT3 signalling and subsequently enhancing downstream senescence. NF-κB and STAT3 inhibitors attenuate oxidative stress-induced senescence in a time-dependent manner. Conditioned medium (CM) from senescent cells rich in SASP factors can induce growth arrest and promote senescence in healthy cells; accordingly, a STAT3 inhibitor blunts the SASP-induced senescence, indicating a positive feedback mechanism via the NF-κB/STAT3 pathway that sustains SASP production and promotes senescence. In addition, we confirmed that AMPK negatively regulates SASP production and senescence development associated with NF-κB/STAT3 inhibition. In summary, our results suggest that AMPK prevents oxidative stress-induced senescence development via inhibiting the NF-κB/SASP/STAT3 signalling mediated positive feedback loop.

应激性早衰 (SIPS) 的特征是分泌多种炎性细胞因子、趋化因子和蛋白酶，这些统称为衰老相关分泌表型 (SASP)。AMP 活化蛋白激酶 (AMPK) 激活有助于 SIPS 预防，可能包括 AMPK 对 SASP 的影响，但控制这种现象的机制尚未阐明。在这项研究中，我们发现 SIPS 伴随着 NF-κB 激活的动态波动，这会诱导 SASP 的产生，同时增强和放大局部 STAT3 信号传导并随后增强下游衰老。NF-κB 和 STAT3 抑制剂以时间依赖性方式减弱氧化应激诱导的衰老。来自富含 SASP 因子的衰老细胞的条件培养基 (CM) 可以诱导健康细胞的生长停滞并促进衰老；因此，STAT3 抑制剂可以减弱 SASP 诱导的衰老，表明存在正反馈机制通过NF-κB/STAT3 通路维持 SASP 的产生并促进衰老。此外，我们证实 AMPK 负向调节与 NF-κB/STAT3 抑制相关的 SASP 产生和衰老发展。总之，我们的结果表明 AMPK通过抑制 NF-κB/SASP/STAT3 信号介导的正反馈回路来防止氧化应激诱导的衰老发展。