{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:07:10Z","timestamp":1788930430383,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007162","name":"Department of Science and Technology of Guangdong Province","doi-asserted-by":"publisher","award":["2025A1515011324"],"award-info":[{"award-number":["2025A1515011324"]}],"id":[{"id":"10.13039\/501100007162","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2025A1515011324"],"award-info":[{"award-number":["2025A1515011324"]}],"id":[{"id":"https:\/\/ror.org\/00tjzgn92","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Longgang District","award":["LGKCYLWS2024-11"],"award-info":[{"award-number":["LGKCYLWS2024-11"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Sterile alpha and Toll\/interleukin-1 receptor motif-containing protein 1 (SARM1) is an inducible NAD-consuming enzyme and execution factor in axon degeneration. Rapid ATP collapse after SARM1 activation, however, is not fully explained by NAD depletion alone. We used SARM1-overexpressing HEK293 cells and the cell-permeant activator CZ-48 to examine SARM1-induced non-apoptotic cell death, termed sarmoptosis. CZ-48 induced cell death that was suppressed by HSP90\/70-annotated ATP-competitive compounds, especially geldanamycin and VER-155008 (VER), without reducing SARM1 abundance. VER preserved NAD and ATP during SARM1 activation but failed to rescue FK866-mediated NAD starvation, thereby distinguishing CZ-48\/SARM1-driven cytotoxicity from generic NAD depletion. In cell-free assays, purified SARM1 reduced ATP levels; this effect was enhanced by SARM1\u2019s activator NMN and attenuated by its pharmacological inhibitors, although the in vitro activity was modest and the reaction products remain to be identified. ATPase-related perturbations, including thapsigargin and bafilomycin A1, also protected cells from CZ-48-induced death, further supporting a central role for ATP collapse in sarmoptosis. iTRAQ proteomics, MitoSOX Red staining, and DiOC6(3) staining revealed that CZ-48 treatment was associated with mitochondrial and metabolic remodeling, mitochondrial ROS accumulation, and mitochondrial depolarization, all of which were mitigated by VER. Collectively, these findings support a convergent ATP-collapse model in which SARM1 activation promotes NAD depletion, directly consumes ATP, and is associated with mitochondrial dysfunction that may amplify ATP-production failure.<\/jats:p>","DOI":"10.3390\/biology15171552","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:07:32Z","timestamp":1788538052000},"page":"1552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond NAD Depletion: SARM1-Induced ATP Collapse Involves Direct ATP Degradation and Mitochondrial Dysfunction and Is Pharmacologically Reversible"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8491-5188","authenticated-orcid":false,"given":"Zhuo","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Biomedical Health Sciences, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1343-0695","authenticated-orcid":false,"given":"Zhi Ying","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3428-9482","authenticated-orcid":false,"given":"Zi-Mei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Biomedical Health Sciences, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center, Medical School, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linru","family":"Shen","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center, Medical School, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6993-0121","authenticated-orcid":false,"given":"Hon Cheung","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Biomedical Health Sciences, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2582-4845","authenticated-orcid":false,"given":"Lei","family":"Fang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center, Medical School, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4564-1912","authenticated-orcid":false,"given":"Yong Juan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Biomedical Health Sciences, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nrm3737","article-title":"Regulated necrosis: The expanding network of non-apoptotic cell death pathways","volume":"15","author":"Berghe","year":"2014","journal-title":"Nat. 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