Human c <scp>GAS</scp> Drives <scp>LINE</scp> ‐1 Transcriptional Activation to Trigger <scp>MAVS</scp> ‐Dependent Cellular Senescence

Long interspersed nuclear element 1 (LINE-1 or L1) retrotransposons pose a significant threat to somatic genomic integrity and are a source of sterile inflammation. Consequently, L1 activity is stringently controlled by multiple regulatory layers to ensure silencing, while its transcriptional derepression is linked to aging and age-related diseases. Recent studies have revealed complex interrelationships between L1 and cGAS, but whether cGAS regulates L1 transcription and its biological significance remains unclear. Here, we demonstrate that human cGAS activates L1 transcription by upregulating the transcriptional regulators CTCF and RUNX3. This cGAS-mediated promotion of L1 transcription is absent in mice due to functional divergence in CTCF and RUNX3. Furthermore, cGAS-mediated elevation of L1 mRNA promotes cellular senescence via MAVS, a key RNA-sensing pathway component. Together, our findings reveal a novel role of cGAS in activating L1 transcription and define a cGAS-L1-MAVS senescence pathway, thereby bridging the noncanonical function of cGAS and the RNA-sensing signaling.