{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:55:25Z","timestamp":1780077325757,"version":"3.54.0"},"reference-count":43,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82405281"],"award-info":[{"award-number":["82405281"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Renal fibrosis is a critical pathogenesis of chronic kidney disease (CKD). Crocin, an active compound derived from saffron (\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">Crocus sativus<\/jats:styled-content>\n                      L\n                    <\/jats:italic>\n                    .), exhibits potent antioxidant and renal protection properties. However, the effects of crocin on renal fibrosis and its underlying mechanisms remain unclear. This study aimed to investigate the potential role and molecular mechanism of crocin in protecting renal cells from ferroptosis and improving renal fibrosis. The study utilized a unilateral ureteral obstruction (UUO) rat model and erastin\u2010induced ferroptosis model in rat renal tubular epithelial (NRK\u201052E) cells to evaluate the effect of crocin on ferroptosis and renal fibrosis. Phospho\u2010specific antibody microarray analysis was conducted to profile crocin\u2010relevant phosphate proteins among 16 signaling pathways. Surface plasmon resonance (SPR) assessments were employed to explore molecular interactions between crocin and mitogen\u2010activated protein kinase kinase 4 (MKK4). Co\u2010immunoprecipitation (Co\u2010IP) experiments were used to investigate interactions between MKK4 and Nrf2. Crocin attenuated renal fibrosis as demonstrated by reducing profibrotic markers in both the UUO model and erastin\u2010treated NRK\u201052E cells. It also significantly inhibited ferroptosis in\u00a0vivo and in\u00a0vitro. Microarray profiling and molecular docking suggested that MKK4 was a critical regulator of ferroptosis and fibrosis. SPR analysis indicated that crocin inhibited p\u2010MKK4 by directly interacting with MKK4. Co\u2010IP further revealed that p\u2010MKK4 interacted with Nrf2, leading to alleviating reactive oxygen species (ROS) levels and subsequently attenuating renal ferroptosis. Crocin exerts protective effects against renal fibrosis and ferroptosis via modulation of phospho\u2010MKK4\/Nrf2\/ferroptosis signaling axis. These findings suggest crocin is a promising renoprotective agent for renal fibrosis, and MKK4 represents a potential target for ferroptosis\u2010related kidney injury.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70092","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T08:01:19Z","timestamp":1758096079000},"page":"5123-5139","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Crocin Attenuates Nrf2\/\n                    <scp>GPX4<\/scp>\n                    Mediated Ferroptosis in Obstructive Nephropathy by Selectively Targeting\n                    <scp>MKK4<\/scp>"],"prefix":"10.1002","volume":"39","author":[{"given":"Ziyun","family":"Xu","sequence":"first","affiliation":[{"name":"Translational Medical Innovation Center Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"},{"name":"Department of Nephropathy Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"},{"name":"School of Chinese Medicine The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Translational Medical Innovation Center Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"},{"name":"Department of Nephropathy Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Wu","sequence":"additional","affiliation":[{"name":"Translational Medical Innovation Center Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"},{"name":"Department of Nephropathy Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[{"name":"Translational Medical Innovation Center Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"},{"name":"Department of Nephropathy Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenfang","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Nephropathy Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minggang","family":"Wei","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine Department The First Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4889-2752","authenticated-orcid":false,"given":"Haiyong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1252-1834","authenticated-orcid":false,"given":"Sheng","family":"Qiang","sequence":"additional","affiliation":[{"name":"Department of Nephropathy Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine  Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2024.118862"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.05.034"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.8380"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.39024"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113297"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/s2214\u2010109x(23)00570\u20103"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.32352"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010025\u201002068\u20104"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.100518"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa041031"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.6564"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2019.112230"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/8841726"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(13)60687\u2010x"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u201000324\u20108"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24087495"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.10.018"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.7.1056"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010020\u20102298\u20102"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102868"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202404585"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.09.033"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658\u2010020\u201000205\u20100"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2023.117189"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103468"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.131102"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2020.1762173"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2016.06.012"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.5638"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156410"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.003"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640\u2010022\u201000500\u2010y"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17300"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.112483"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201007260\u2010x"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.59404"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.116881"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.71595"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109235"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202304098"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010021\u201004137\u20101"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2024.118264"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.757729"}],"container-title":["Phytotherapy Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70092","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ptr.70092","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70092","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T11:05:47Z","timestamp":1769857547000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ptr.70092"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,17]]},"references-count":43,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1002\/ptr.70092"],"URL":"https:\/\/doi.org\/10.1002\/ptr.70092","archive":["Portico"],"relation":{},"ISSN":["0951-418X","1099-1573"],"issn-type":[{"value":"0951-418X","type":"print"},{"value":"1099-1573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,17]]},"assertion":[{"value":"2025-03-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}