{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:01:57Z","timestamp":1789970517935,"version":"4.0.1"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"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>Cerebral microvascular injury and ferroptosis are increasingly implicated in diabetic encephalopathy (DE). This study investigated whether curcumin (Cur) alleviates DE by attenuating cerebral microvascular ferroptosis and examined the involvement of KEAP1\/Nrf2-related signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Diabetic rats were treated with Cur for 8 weeks, with metformin as a positive control. Metabolic parameters, cognitive function, hippocampal histopathology, cerebral microvascular tight-junction proteins, oxidative stress, and ferroptosis-related markers were evaluated. Brain untargeted metabolomics and exploratory network analysis were integrated with molecular experiments to generate and experimentally evaluate mechanistic hypotheses. An HGHF-induced bEnd.3 cell model, together with erastin, ferrostatin-1, and ML385 interventions, was used for\n                      <jats:italic>in vitro<\/jats:italic>\n                      validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Cur improved metabolic abnormalities, cognitive impairment, and hippocampal injury in diabetic rats. Untargeted metabolomics revealed ferroptosis-related metabolic alterations, including changes in glutathione-, taurine-, and polyunsaturated fatty acid-related metabolism. Cur reduced oxidative stress, restored tight-junction protein expression, and attenuated ferroptosis-related changes in cerebral microvessels. Experimental analyses further showed coordinated regulation of KEAP1, NRF2, HO-1, GCLC, GPX4, ACSL4, and NOX4\n                      <jats:italic>in vivo<\/jats:italic>\n                      . In HGHF-treated bEnd.3 cells, Cur reduced lipid peroxidation and Fe\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation, improved antioxidant capacity, attenuated mitochondrial injury, and restored tight-junction protein expression. Erastin aggravated, whereas ferrostatin-1 attenuated, HGHF-induced ferroptosis-related injury, and ML385 partially attenuated the protective effects of Cur.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Cur alleviated DE-related metabolic, cognitive, and hippocampal abnormalities and attenuated ferroptosis-associated cerebral microvascular injury. KEAP1\/Nrf2-related signalling contributed to these protective effects. These findings link Cur-mediated neuroprotection to the regulation of cerebral microvascular ferroptosis and support its further investigation in diabetes-associated cognitive impairment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1914347","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:35:44Z","timestamp":1789968944000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Curcumin alleviates diabetic encephalopathy by attenuating cerebral microvascular ferroptosis: involvement of KEAP1\/Nrf2 signalling"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhaoqi","family":"Zhang","sequence":"first","affiliation":[{"name":"The First Clinical Medical College, Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingru","family":"Zhao","sequence":"additional","affiliation":[{"name":"Military Retirement Clinic, Jinan Municipal Government Hospital","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang","family":"Gao","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangwei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Imaging, Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Yv","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Wu","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moji","family":"Wangchen","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]},{"name":"Department of Neurology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"CD003804","DOI":"10.1002\/14651858.CD003804.pub2","article-title":"Effect of the treatment of type 2 diabetes mellitus on the development of cognitive impairment and dementia","volume":"6","author":"Areosa Sastre","year":"2017","journal-title":"Cochrane Database Syst. 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