Facilitated DNA damage repair as an emerging therapeutic strategy for inflammatory and fibrotic diseases.

DNA damage arising from metabolic stress, oxidative injury, and impaired genome maintenance emerges as a common driver for chronic inflammatory and fibrotic diseases across multiple organs. While rapid and effective DNA damage repair is essential for the response to acute injury, sustained activation of these pathways promotes cellular senescence, sterile inflammation and fibroblast activation, ultimately driving fibrogenesis and pathological tissue remodelling. In recent years, DNA repair processes, particularly base excision repair in both the nucleus and mitochondria, receive increasing attention as modulators of inflammatory and fibrotic outcomes. Here, we review the molecular mechanisms by which unresolved nuclear and mitochondrial DNA lesions translate into chronic inflammation and fibrosis across skin, liver, lung and cardiovascular tissues. We discuss the roles of chromatin context, NAD+ availability, repair intermediates and mitochondrial genome instability in shaping DNA damage responses and highlight emerging chemical biology strategies to facilitate DNA repair, including organocatalytic switches of DNA glycosylases, DNA polymerase γ (POLG) activators or small molecules targeting the inflammasome or cGAS-STING pathway. Based on the available evidence from animal models and organotypic human in vitro cultures, we propose that facilitated DNA repair may represent a promising therapeutic strategy for chronic inflammatory and fibrotic diseases. This perspective positions genome maintenance pathways as upstream intervention points for chronic inflammatory and fibrotic diseases.