{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:24:16Z","timestamp":1789986256626,"version":"4.0.1"},"reference-count":23,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Kaempferol has been shown to be beneficial in the treatment of Alzheimer's disease (AD) in animal models. However, the action mechanism remains unclear. AKR1B1 has been identified as a target of kaempferol, initially suggested by the Therapeutic Target Database, DrugBank, and PubChem, and subsequently confirmed through experimental validation. Kaempferol treatment facilitated the expression of AKR1B1 in PC12 cells exposed to A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    . Kaempferol treatment mitigated the A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    \u2010induced increases in Fe\n                    <jats:sup>2+<\/jats:sup>\n                    , MDA, and lipid ROS and A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    \u2010induced decreases in GSH synthesis and SOD activity. The reduction in ferroptosis\u2010related proteins (GPX4, NQO1, SLC7A11, AKR1C1, and AKR1C3) and the inhibition of Nrf2 nuclear translocation and Nrf2\/HO\u20101 signaling caused by A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    were also reversed by kaempferol. Overexpressing AKR1B1 led to decreased levels of Fe\n                    <jats:sup>2+<\/jats:sup>\n                    , MDA, and lipid ROS, along with increased GSH synthesis and SOD activity in A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    \u2010treated cells, although these effects were negated by Nrf2 inhibition. The upregulation of GPX4 and AKR1C3 by AKR1B1 overexpression was also reversed when Nrf2 expression was inhibited. Notably, silencing AKR1B1 counteracted the protective effects of kaempferol against A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    \u2010induced neuronal ferroptosis. In\u00a0vivo studies revealed that kaempferol improved cognitive impairments, reduced deposition of A\u03b2 and p\u2010Tau, and alleviated neuronal ferroptosis in the hippocampal tissues of an AD mouse model in a dose\u2010dependent manner, effects that were diminished by inhibiting AKR1B1 expression. Following kaempferol treatment, the levels of GPX4 and AKR1C3 in the hippocampus of AD mice were found to be reduced. Overall, our findings indicate that kaempferol treatment enhances cognitive function and mitigates pathological alterations in AD mice by inhibiting neuronal ferroptosis through the activation of the Nrf2\/HO\u20101\/GPX4\/AKR1C3 signaling via upregulation of AKR1B1. This research supports the need for further investigation and clinical exploration of kaempferol.\n                  <\/jats:p>","DOI":"10.1002\/prp2.70255","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:46:21Z","timestamp":1777607181000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Kaempferol Improves Alzheimer's Disease by Inhibiting Neuronal Ferroptosis via Activating\n                    <scp>GPX4<\/scp>\n                    \/\n                    <scp>AKR1C3<\/scp>\n                    Signaling Pathway"],"prefix":"10.1002","volume":"14","author":[{"given":"Le","family":"Li","sequence":"first","affiliation":[{"name":"College of Chemistry &amp; Pharmacy Northwest A&amp;F University  Yangling Shaanxi China"},{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology Shihezi University  Shihezi Xinjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manying","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology Shihezi University  Shihezi Xinjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiale","family":"Tao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology Shihezi University  Shihezi Xinjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology Shihezi University  Shihezi Xinjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology Shihezi University  Shihezi Xinjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3135-8542","authenticated-orcid":false,"given":"Shiguo","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Chemistry &amp; 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