TRF2 enriched cytoplasmic chromatin drives cGAS-STAT1-mediated inflammation in senescence

Telomere dysfunction, persistent DNA damage, and chronic inflammation are interconnected hallmarks of cellular senescence, but their molecular links remains poorly defined. Here, we find that senescent cells accumulate telomeric protein TRF2-enriched cytoplasmic chromatin fragments (CCFs), which co-localize with γH2AX and H3K27me3 but lack DNA repair proteins, indicating persistent, unrepaired damage. Inflammatory stress, nuclear lamina dysfunction, and progeroid mutations compromise nuclear integrity, promoting nuclear rupture and extrusion of TRF2-bound nuclear DNA fragments into the cytoplasm. TRF2-enriched CCFs engage the cGAS-STAT1 pathway, sustaining SASP production and reinforcing senescence. Pharmacological inhibition of JAK-STAT or metformin treatment suppressed TRF2-enriched CCFs, reduced cGAS-STAT1 activation, DNA damage markers, and SASP. Our study uncovers TRF2-enriched CCFs as a previously unrecognized source of nuclear-derived DNA in senescent cells. We propose that damaged telomeric DNA extruded into the cytoplasm drives chronic immune activation and inflammation, linking nuclear instability to accelerated aging.