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Using a mouse skin injury model combined with spatial transcriptomics and functional assays, we identify radical s\u2010adenosyl methionine domain containing 2\u00a0(RSAD2) as a critical regulator of mtDNA\u2010driven inflammation in macrophages. Mechanistically, RSAD2 directly binds the N\u2010terminal domain of cytidylate monophosphate kinase 2 (CMPK2), a rate\u2010limiting enzyme for mtDNA synthesis, and dually modulates its activity: it inhibits K63\u2010linked ubiquitination to stabilize CMPK2, and recruits casein kinase 2 alpha 2 (Csnk2a2) to promote CMPK2 phosphorylation, thereby enhancing mtDNA production. Newly synthesized mtDNA amplifies inflammation through two coordinated pathways: activation of a cGAS\u2010STING\u2010IRF3\u2010RSAD2 feedforward loop, and synergistic activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. These pathways orchestrate inflammatory amplification in macrophages to modulate skin repair. Our work establishes macrophage RSAD2 as a central hub that coordinates two mtDNA\u2010dependent inflammatory axes, revealing a feedforward immuno\u2010metabolic circuit with broad implications for inflammation\u2010driven diseases.<\/jats:p>","DOI":"10.1002\/advs.77416","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:54:45Z","timestamp":1787990085000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage RSAD2 Couples mtDNA Synthesis With a Self\u2010Amplifying Inflammatory Circuit to Orchestrate Tissue Repair"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3221-5954","authenticated-orcid":false,"given":"Haomiao","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of Forensic Pathology China Medical University School of Forensic Medicine  Shenyang China"},{"name":"Liaoning Province Key Laboratory of Forensic Bio\u2010Evidence 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