Identification of a small molecule SR9009 that activates NRF2 to counteract cellular senescence |
| |
| Authors: | Li&#x;Bin Gao Ya&#x;Hong Wang Zhi&#x;Hua Liu Yu Sun Peng Cai Qing Jing |
| |
| Institution: | 1. CAS Key Laboratory of Tissue Microenvironment and Tumor, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai China ; 2. Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen China ; 3. Xiamen Key Laboratory of Physical Environment, Xiamen China |
| |
| Abstract: | The senescence‐associated secretory phenotype (SASP) is a striking characteristic of senescence. Accumulation of SASP factors causes a pro‐inflammatory response linked to chronic disease. Suppressing senescence and SASP represents a strategy to prevent or control senescence‐associated diseases. Here, we identified a small molecule SR9009 as a potent SASP suppressor in therapy‐induced senescence (TIS) and oncogene‐induced senescence (OIS). The mechanism studies revealed that SR9009 inhibits the SASP and full DNA damage response (DDR) activation through the activation of the NRF2 pathway, thereby decreasing the ROS level by regulating the expression of antioxidant enzymes. We further identified that SR9009 effectively prevents cellular senescence and suppresses the SASP in the livers of both radiation‐induced and oncogene‐induced senescence mouse models, leading to alleviation of immune cell infiltration. Taken together, our findings suggested that SR9009 prevents cellular senescence via the NRF2 pathway in vitro and in vivo, and activation of NRF2 may be a novel therapeutic strategy for preventing cellular senescence. |
| |
| Keywords: | cellular senescence DNA damage NRF2 ROS SASP SR9009 |
|
|
