IRF3 activates RB to authorize cGAS-STING-induced senescence and mitigate 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. DLD1 wild type (WT) and IRF3 knock out (KO) cells treated with ddH2O or HU for two replicates are performed mRNA sequencing.