On February 28, 2024, Science Advances published a collaborative research work by the Pinglong Xu Laboratory, Bing Xia Laboratory, Xin-Hua Feng Laboratory, and Li Shen Laboratory. Titled IRF3 activates RB to authorize cGAS-STING-induced senescence and mitigate liver fibrosis, this research represents a pioneering effort to elucidate an unrecognized mechanism of cGAS-STING-induced cellular senescence and its significant physiological implication in limiting liver fibrosis.
Cytosolic dsDNA surveillance by cGAS-STING signaling triggers autophagy, biased mRNA translation, cellular senescence, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that IRF3, activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a well-known tumor suppressor and key cell cycle regulator. The IRF3-RB interaction attenuates CDK4/6-mediated hyperphosphorylation of RB that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within CCl4 or bile duct ligation (BDL)-induced murine models, pushing activated HSCs towards senescence. Accordingly, global IRF3 knockout or conditional deletion of IRF3 in HSCs aggravated liver fibrosis, a process mitigated by an FDA-approved CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.
Dr. Qirou Wu and Ph.D. candidate Xiaohong Leng in Xu laboratory are the co-first authors, with corresponding authors being Professors Xu Pinglong, Xia Bing, Feng Xin-Hua, and Shen Li, and have collaborated with Drs. Wang Xiaoqian, Lin Aifu, Lin Xia, Liang Tingbo. This research was funded by key projects and Outstanding Young Scientists projects from the National Natural Science Foundation (31830052, 32321002, and 31725017 to P.X.), and the MoST key R&D program (2021YFA1301401 to P.X.), and was carried out and completed at Zhejiang University.
The IRF3-RB signaling axis mediates cGAS-STING-controlled senescence of hepatic stellate cells to limit liver fibrosis
Article link: https://www.science.org/doi/10.1126/sciadv.adj2102
