{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T08:49:17Z","timestamp":1791449357353,"version":"4.3.3"},"reference-count":41,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":34,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioFactors"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Sepsis\u2010associated acute kidney injury (SAKI) lacks mechanism\u2010based therapies, with upstream ferroptosis regulators undefined. This study investigated growth differentiation factor 15 (GDF15) as a suppressor of TLR4\u2010MyD88\u2010NF\u2010\u03baB signaling and associated ferroptosis. Differential GDF15 expression was identified by integrated analysis of three GEO datasets (GSE232404, GSE30718, GSE44925) and validated in SAKI patient kidney tissue (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930 vs. controls\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200925) and in kidneys from cecal ligation and puncture (CLP) mice. CLP mice received recombinant GDF15 (rmGDF15) (50\u2009ng\/kg\u2009ip); renal function (Scr\/BUN), histology, kidney injury molecule\u20101 (KIM\u20101), serum TNF\u2010\u03b1\/IL\u20101\u03b2\/IL\u20106 (ELISA), and 7\u2010day survival were assessed. Oxidative stress\/ferroptosis was quantified by DCFH\u2010DA ROS imaging and kits (MDA, GSH, SOD, NADPH, Fe, GPX4 activity); TLR4\u2010MyD88\u2010NF\u2010\u03baB by qRT\u2010PCR, Western blot, and Immunohistochemistry. LPS (1\u2009\u03bcg\/mL, 48\u2009h)\u2010stimulated HK\u20102 cells underwent shGDF15 lentiviral knockdown (puromycin 2\u2009\u03bcg\/mL)\u2009\u00b1\u2009TAK242 (1\u2009\u03bcM); viability (CCK\u20108), apoptosis (Annexin V\/PI flow), cytokines (ELISA\/qRT\u2010PCR), ROS, ferroptosis markers, and pathway activation were evaluated. GDF15 was upregulated in SAKI datasets, patient kidney tissue, and CLP kidneys. GDF15 supplementation improved survival, lowered Scr\/BUN and KIM\u20101, attenuated tubular injury, and reduced systemic proinflammatory cytokines. It decreased renal ROS, MDA and Fe while restoring GSH, SOD, NADPH, GPX4 activity, and SLC7A11 expression, and suppressed TLR4\u2010MyD88\u2010NF\u2010\u03baB signaling. In HK\u20102 cells, GDF15 silencing aggravated LPS\u2010induced loss of viability, apoptosis, cytokine release, oxidative stress, and ferroptosis markers, all reversed by TAK242. In conclusion, GDF15 is a stress\u2010inducible renoprotective factor that suppresses TLR4 signaling, ferroptosis markers, and inflammation in SAKI, suggesting exogenous administration as a promising therapeutic strategy.\n                  <\/jats:p>","DOI":"10.1002\/biof.70138","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T02:53:50Z","timestamp":1785898430000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Growth Differentiation Factor 15 (\n                    <scp>GDF15<\/scp>\n                    ) Protects Against Sepsis\u2010Associated Acute Kidney Injury via Suppression of\n                    <scp>TLR4<\/scp>\n                    \u2010\n                    <scp>MyD88<\/scp>\n                    \u2010\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    Signaling and Ferroptosis"],"prefix":"10.1002","volume":"52","author":[{"given":"Chengyi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Nephrology Changzhou Geriatric Hospital Affiliated to Soochow University  Changzhou Jiangsu China"},{"name":"Department of Nephrology Changzhou No. 7 People's Hospital  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8387-3848","authenticated-orcid":false,"given":"Le","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Nephrology Changzhou Geriatric Hospital Affiliated to Soochow University  Changzhou Jiangsu China"},{"name":"Department of Nephrology Changzhou No. 7 People's Hospital  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Di","sequence":"additional","affiliation":[{"name":"Department of Nephrology The Third Affiliated Hospital of Soochow University  Changzhou Jiangsu China"},{"name":"Department of Nephrology The First People's Hospital of Changzhou  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiangyan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Changzhou Geriatric Hospital Affiliated to Soochow University  Changzhou Jiangsu China"},{"name":"Department of Nephrology Changzhou No. 7 People's Hospital  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"1","key":"e_1_2_11_2_1","first-page":"67","article-title":"Sepsis Definition: What's New in the Treatment Guidelines","volume":"61","author":"Srzi\u0107 I.","year":"2022","journal-title":"Acta Clinica 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