{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:03:38Z","timestamp":1789621418036,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Ischemia\/reperfusion (IR) injury is a pivotal contributor to acute lung injury (ALI) for which effective treatment options are currently lacking. Following ischemia, succinate accumulation and reoxidation by succinate dehydrogenase (SDH) during reperfusion induce excessive reactive oxygen species production, causing significant tissue damage. Dimethyl malonate (DMM), a competitive SDH inhibitor, has shown promise in treating various forms of IR-induced damage, but its effects on IR-induced ALI remain unexplored. To our knowledge, this is the first study to demonstrate in an\n                      <jats:italic>ex vivo<\/jats:italic>\n                      lung perfusion model that pharmacological inhibition of SDH via DMM alleviates IR-induced ALI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Isolated rat lungs subjected to ischemia (40\u00a0min) followed by reperfusion (60\u00a0min) were treated with various DMM concentrations (2\u00a0mM, 4\u00a0mM, and 8\u00a0mM) and 8\u00a0mM dimethyl succinate (DMS, a cell-permeable derivative of succinate). At the end of the experiment, bronchoalveolar lavage fluid and lung tissues were collected and analyzed. Target engagement was verified by measuring SDH enzymatic activity. Additionally, mouse lung epithelial (MLE)-12 cells underwent hypoxia-reoxygenation (HR) to investigate the cellular impact of DMM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Metabolomic analysis revealed that succinate accumulated significantly in lung tissue after IR injury. DMM treatment effectively suppressed the IR-induced elevation of SDH enzymatic activity in both lung tissues and MLE-12 cells. Consequently, DMM dose-dependently reduced pulmonary edema and protein levels in bronchoalveolar lavage fluid. DMM also improved lung injury scores and attenuated proinflammatory cytokine production, apoptosis, and oxidative stress. These protective effects were associated with upregulated Nrf2\/HO-1 activity and inhibited NF-\u03baB signaling, all of which were reversed by DMS supplementation. Similar results were observed in MLE-12 cells following HR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that inhibiting SDH with DMM has considerable potential for mitigating IR-induced ALI. The therapeutic application of DMM could be a promising approach for alleviating IR-induced ALI severity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1746514","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:29:10Z","timestamp":1789619350000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dimethyl malonate suppresses succinate dehydrogenase to alleviate ischemia\/reperfusion-induced acute lung injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Shih-En","family":"Tang","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University","place":["Taipei, Taiwan"]},{"name":"Institute of Aerospace and Undersea Medicine, National Defense Medical University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Yu","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Aerospace and Undersea Medicine, National Defense Medical University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Ping","family":"Pao","sequence":"additional","affiliation":[{"name":"The Graduate Institute of Medical Sciences, National Defense Medical University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Jye","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-I","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.3390\/antiox13121579","article-title":"Succinate regulates endothelial mitochondrial function and barrier integrity","volume":"13","author":"Atallah","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"101640","DOI":"10.1016\/j.redox.2020.101640","article-title":"Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury","volume":"36","author":"Beach","year":"2020","journal-title":"Redox Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1001\/jama.2016.0291","article-title":"Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries","volume":"315","author":"Bellani","year":"2016","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1016\/j.jnutbio.2011.10.012","article-title":"Inhibition of NF-kappaB nuclear translocation via HO-1 activation underlies alpha-tocopheryl succinate toxicity","volume":"23","author":"Bellezza","year":"2012","journal-title":"J. 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