Abstract Body: Organ failure after injury-induced fibrosis is a major world-wide health care burden with few therapeutic options. Acomys (spiny mice) is an ancient rodent species native to Africa and the Middle East that has evolved a remarkable wound healing response to tissue damage. Following prolonged ischemia, burns, ablations, or surgical trauma spiny mice will fully regenerate the lost tissue and restore complex organ structure and function without forming function-degrading fibrotic scars. This sharply contrasts with humans and other mammals that respond to the same injuries with robust inflammation and deposition of a collagen-rich fibrotic matrix with consequent loss of organ architecture and function. The scale of this problem of fibrosis-induced loss of organ function across major organ systems in human populations both young and old is enormous. Using Oxford nanopore long-read DNA sequencing, we obtained the complete sequence of the spiny mouse genome and identified 38 genes under purifying selection in Acomys compared to rodent genomes across the Muridae family. In response to unilateral ureteral obstruction (UUO) or ischemia-reperfusion injuries (IRI) to the kidney, we found that mice (B6 or CD1) rapidly developed interstitial fibrosis that progressed to renal failure by 14-21d, while the same injuries to spiny mice produced no fibrosis and rapid regeneration of nephron structure and function over the same time period. RNAseq analysis at 2d after UUO injury showed 843 differentially regulated genes between Mus and Acomys, suggesting the spiny mouse genome is poised to initiate scarless regeneration immediately after injury. We are applying multi-omics assays and comparative genomics analysis across animals that do or do not regenerate organ damage without fibrosis to decode the regulatory logic of scar-free regeneration in Acomys. Results from these experiments will be discussed.