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Here, we established a streptozotocin\u2010induced DW mouse model, and combined untargeted metabolomics with in\u00a0vitro and in\u00a0vivo validations to decipher PNS's therapeutic mechanism and active ingredients. In\u00a0vivo, PNS dose\u2010dependently accelerated wound closure, enhanced collagen deposition, and improved glucose tolerance and insulin sensitivity in diabetic mice, without affecting body weight or random blood glucose. Mechanistically, PNS inhibited Ephx2 expression (at both mRNA and protein levels) in macrophages to upregulate 11,12\u2010EET, thus mitigating wound inflammation, NLRP3 inflammasome\u2010mediated pyroptosis, and mitochondrial dysfunction. In\u00a0vitro, the protective effects of PNS on macrophage mitochondrial function and pyroptosis were not enhanced by Ephx2 inhibitor TPPU, but completely abolished by 11,12\u2010EET antagonist 14,15\u2010EEZE. Furthermore, five major saponins (R1, Rg1, Re, Rb1, Rd) from PNS were identified as active ingredients, all exerting pro\u2010healing effects in DW mice. Conclusively, PNS accelerates DW healing via regulating the macrophage Ephx2\/11,12\u2010EET axis to preserve mitochondrial homeostasis and inhibit pyroptosis, supporting its therapeutic potential for diabetic foot ulcers.\n                  <\/jats:p>","DOI":"10.1002\/fsn3.72494","type":"journal-article","created":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T04:49:56Z","timestamp":1792212596000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>Panax notoginseng<\/i>\n                    Saponins Accelerate Diabetic Wound Repair by Minimizing Mitochondrial Dysfunction and Inhibiting Pyroptosis of Macrophage via Regulating Ephx2\/11,12\u2010\n                    <scp>EET<\/scp>\n                    Axis"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4353-0127","authenticated-orcid":false,"given":"Nan","family":"Chen","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)  Hangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)  Hangzhou P. R. China"},{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao\u2010di Herbs  Beijng P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai\u2010hua","family":"Sun","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)  Hangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9006-8160","authenticated-orcid":false,"given":"Tong","family":"Hou","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)  Hangzhou P. R. China"},{"name":"School of Public Health Zhejiang Chinese Medical University  Hangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2025.159668"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.70"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.10578"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423\u2010022\u201000919\u20105"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010021\u201004379\u2010z"},{"key":"e_1_2_13_7_1","volume-title":"StatPearls","author":"Britto E. 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