A Science paper showed that unrepaired DNA‑protein crosslinks (DPCs) accumulate in cells lacking the SPRTN protease, triggering micronuclei formation and activation of the cGAS‑STING innate immune pathway. In mouse models with an RJALS‑linked SPRTN mutation, DPC accumulation produced embryonic lethality and premature aging features; pharmacologic or genetic inhibition of cGAS‑STING rescued embryonic viability and ameliorated aging phenotypes. The study combined biochemical assays, proximity labeling, and mutant mouse genetics to position SPRTN as a key DPC repair protease during replication and mitosis. Loss of SPRTN led to interferon‑stimulated gene upregulation and sustained inflammatory signaling mediated by innate DNA sensing. These data identify innate immune activation downstream of DPC accumulation as a tractable target for treating progeroid syndromes and suggest cGAS‑STING inhibitors may have therapeutic value in disorders of genome maintenance.