{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:15:50Z","timestamp":1788156950730,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"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>Introduction<\/jats:title>\n                    <jats:p>Diabetes mellitus complicated with depression (T2DD) is different from a single disease. It leads to more severe damage to nerve cells and cognitive dysfunction, and has a poor prognosis. Existing evidence indicates that ferroptosis\u2014a form of programmed cell death driven by iron accumulation and lipid peroxidation\u2014is involved in both diabetes and depression. Glutathione peroxidase 4 (GPX4) and long-chain acyl-CoA synthetase family member 4 (ACSL4) are key regulators of ferroptosis, but their roles in T2DD-associated neural damage remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we established a T2DD rat model using a high-fat diet combined with streptozotocin injection and chronic unpredictable mild stress and performed behavioral tests to assess depressive-like behaviors. Meanwhile, HT22 hippocampal neuronal cells were exposed to high glucose and corticosterone to simulate an\n                      <jats:italic>in vitro<\/jats:italic>\n                      model of T2DD. We investigated the role of the GPX4\/ACSL4 axis in ferroptosis in the primary somatosensory cortex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vivo<\/jats:italic>\n                      , T2DD rats exhibited reduced spontaneous activity, aggravated neuronal damage, Fe\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation in the cortical region, elevated oxidative stress, upregulation of CSL4\/NCOA4 expression, and downregulation of GPX4\/SLC7A11 expression, indicating that T2DD exacerbates neural damage.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , high glucose (50 mM) and corticosterone (200 \u03bcM) synergistically reduced HT22 cell viability, increased reactive oxygen species (ROS) levels, and induced JC-1 and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      alterations suggesting mitochondrial depolarization and aggravated mitochondrial damage, further complementing the above conclusions. Notably, treatment with the ACSL4 inhibitor AS252424 reversed the abnormalities in reactive oxygen species, Fe\n                      <jats:sup>2+<\/jats:sup>\n                      , and malondialdehyde levels induced by RSL3 (a GPX4 inhibitor), while restoring glutathione (GSH) levels and Adenosine Triphosphate suggesting that dysregulation of the GPX4\/ACSL4 axis may be the central mechanism underlying ferroptosis and neuronal damage in T2DD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study reveals the role of ferroptosis in the T2DD model and provides new insights into therapeutic interventions targeting lipid metabolism pathways.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1891812","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:41:04Z","timestamp":1788154864000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dysregulation of the GPX4\/ACSL4 axis mediates ferroptosis in neurons of T2DD rats"],"prefix":"10.3389","volume":"17","author":[{"given":"Yi","family":"Wang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Ningxia Uyghur Autonomous Region People's Hospital","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Lei","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucheng","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Affiliated Shizuishan First People's Hospital of Ningxia Medical University","place":["Shizuishan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]},{"name":"Department of Pathology, School of Basic Medical Science, Guangdong Medical University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s11064-021-03442-7","article-title":"Liraglutide alleviates cognitive deficit in db\/db mice: involvement in oxidative stress, iron overload, and ferroptosis","volume":"47","author":"An","year":"2022","journal-title":"Neurochem. 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