{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T18:46:30Z","timestamp":1793126790533,"version":"4.5.0"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"2","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2023YFA1800400"],"award-info":[{"award-number":["2023YFA1800400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Science Foundation of China","doi-asserted-by":"crossref","award":["32370825 92249302 and 92049301"],"award-info":[{"award-number":["32370825 92249302 and 92049301"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,1,13]]},"abstract":"<jats:p>\n                    Diabetic peripheral neuropathy (DPN), the most common complication of diabetes, lacks effective treatments and is characterized by early axonal degeneration mediated by sterile alpha and Toll\/interleukin receptor motif-containing protein 1 (SARM1). Here, we identify a regulatory mechanism of SARM1\u2019s NAD\n                    <jats:sup>+<\/jats:sup>\n                    -cleaving activity via acetylation at lysine 641 (K641). In high-glucose conditions, SIRT3 deacetylates SARM1 at K641, enhancing its NAD\n                    <jats:sup>+<\/jats:sup>\n                    cleavage activity and exacerbating axonal damage. In type 2 diabetic (T2DM) mice, acetylation of SARM1 at K641 (K641Ac) or\n                    <jats:italic toggle=\"yes\">Sirt3<\/jats:italic>\n                    knockout mitigates hypoalgesia, intraepidermal nerve fiber loss in footpad skin, and axonal growth retardation in dorsal root ganglia. These interventions also attenuate ROS accumulation, ATP depletion, and NAD\n                    <jats:sup>+<\/jats:sup>\n                    decline, conferring protection against DPN pathology. Notably, wild-type SARM1 expression reverses the protective effects of\n                    <jats:italic toggle=\"yes\">Sirt3<\/jats:italic>\n                    ablation in T2DM mice, whereas SARM1 K641Q does not. Our findings establish that SIRT3-mediated deacetylation of SARM1 at K641 drives axonal degeneration in DPN, and enhancing K641 acetylation mitigates disease progression. This study uncovers a critical posttranslational regulation of SARM1 and suggests that targeting the SIRT3\u2013SARM1 axis may offer therapeutic potential for DPN and related neurodegenerative conditions.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2517110123","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T18:46:07Z","timestamp":1767984367000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Hyperglycemia promotes SIRT3-mediated deacetylation of SARM1 to exacerbate diabetic peripheral neuropathy in mice"],"prefix":"10.1073","volume":"123","author":[{"given":"Chunyu","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9529-6655","authenticated-orcid":false,"given":"Liliang","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxi","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuefeng","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4932-4343","authenticated-orcid":false,"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4564-1912","authenticated-orcid":false,"given":"Yongjuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzhong","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-4607","authenticated-orcid":false,"given":"Wei","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0092-1"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.02.005"},{"key":"e_1_3_4_3_2","article-title":"Enhanced glucose control for preventing and treating diabetic neuropathy","volume":"2012","author":"Callaghan B. 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Chen Hyperglycemia promotes SIRT3-mediated deacetylation of SARM1 to exacerbate diabetic peripheral neuropathy in mice. Figshare. https:\/\/doi.org\/10.6084\/m9.figshare.c.8220263.v3. 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