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It counteracts inflammation and oxidative stress in inflammatory skin diseases, obesity, and associated metabolic disorders, in part by inhibiting the kallikrein proteases KLK7 and KLK14. Vaspin binds the cell\u2010surface low\u2010density lipoprotein receptor\u2010related protein 1 (LRP1) with nanomolar affinity, and is rapidly internalized into adipocytes and other cells. We found intracellular vaspin partially localized in the nucleus. Since vaspin binds heparin and inorganic polyphosphates, we investigated the DNA binding of vaspin. Using DNA\u2010affinity chromatography and differential radial capillary action of ligand assays, we found high\u2010affinity binding to random sequences of single\u2010 and double\u2010stranded DNA for both vaspin and KLK7. Furthermore, KLK7 inhibition was accelerated fivefold in the presence of DNA molecules at least 40 bases in length. We previously identified the heparin\u2010binding site at a basic patch on the central beta\u2010sheet A of vaspin. In the current work, we determined the crystal structure of polyphosphate P45\u2010bound vaspin, which confirmed previously identified residues mutated to generate a nonheparin\u2010binding (NHB) vaspin variant. While NHB vaspin failed to bind heparin and polyP45, it still bound DNA with high affinity and accelerated protease inhibition. Mutation of closely spaced basic residues in helix A and helix G did not significantly alter DNA binding. In conclusion, we have identified vaspin as the second human DNA\u2010binding serpin. While the exact mode of the nonspecific interaction remains unclear, it accelerates protease inhibition and likely contributes to the nuclear localization observed for internalized vaspin and may allow for intracellular effects.<\/jats:p>","DOI":"10.1111\/febs.70270","type":"journal-article","created":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T17:16:13Z","timestamp":1758474973000},"page":"2119-2132","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Vaspin identified as a\n                    <scp>DNA<\/scp>\n                    \u2010binding serpin with functional consequences for protease inhibition"],"prefix":"10.1111","volume":"293","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0508-0463","authenticated-orcid":false,"given":"Kevin","family":"M\u00f6hlis","sequence":"first","affiliation":[{"name":"Helmholtz Institute for Metabolic Obesity and Vascular Research (HI\u2010MAG) of the Helmholtz Zentrum 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