{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:01:05Z","timestamp":1790773265976,"version":"4.1.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>Diabetic nephropathy is a leading cause of end-stage renal disease, with podocyte loss being a critical event in its progression. However, the dominant molecular mechanism driving podocyte loss remains elusive, hindering targeted therapy. We aimed to identify the key pathways of podocyte failure in human diabetic nephropathy and investigate metformin\u2019s therapeutic potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed an integrative multi-omics approach, including single-nucleus RNA-seq (snRNA-seq) of 156,043 human kidney nuclei from individuals with diabetic nephropathy and healthy control individuals,\n                      <jats:italic>db\/db<\/jats:italic>\n                      mouse models of diabetic nephropathy, spatial metabolomics, in vitro podocyte cultures, and targeted urinary metabolomics in individuals with diabetic nephropathy and healthy control individuals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>snRNA-seq identified ferroptosis and fatty acid metabolic dysregulation as the most enriched pathways within podocytes, mechanistically linked to the MAPK14\u2013solute carrier family 7 member 11 (SLC7A11)\u2013glutathione peroxidase 4 (GPX4) axis. In murine diabetic nephropathy models and in vitro, metformin directly inhibited this MAPK14\u2013SLC7A11\u2013GPX4 axis, suppressed podocyte ferroptosis (including restoration of GPX4 and SLC7A11 expression and reduction of p-p38 and lipid peroxidation) and restored compartment-specific renal lipid accumulation as shown by spatial metabolomics. Clinically, we identified and validated a urinary fatty acid signature, with palmitoylcarnitine as a key biomarker (AUC 0.974, calculated from receiver operating characteristic curves), correlating with disease indices including blood glucose, eGFR, serum creatinine and blood urea nitrogen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Our study reveals podocyte ferroptosis to be a central pathogenic event in human diabetic nephropathy, repositioning metformin as a direct ferroptosis inhibitor that preserves podocyte integrity via the MAPK14\u2013SLC7A11\u2013GPX4 axis. Furthermore, we provide a high-performance urinary biomarker, offering a direct translational link toward targeted anti-ferroptosis therapies and non-invasive diagnostics for diabetic nephropathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06821-3","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:14:50Z","timestamp":1785777290000},"page":"3312-3327","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin protects podocytes by inhibiting the MAPK14\u2013SLC7A11\u2013GPX4 axis and dysregulation of fatty acid metabolism"],"prefix":"10.1007","volume":"69","author":[{"given":"Shi","family":"Qiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sifan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songqi","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqiang","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3784-4472","authenticated-orcid":false,"given":"Aihua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"issue":"10225","key":"6821_CR1","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/S0140-6736(20)30045-3","volume":"395","author":"GBD Chronic Kidney Disease Collaboration","year":"2020","unstructured":"GBD Chronic Kidney Disease Collaboration (2020) Global, regional, and national burden of chronic kidney disease, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 395(10225):709\u2013733. https:\/\/doi.org\/10.1016\/S0140-6736(20)30045-3","journal-title":"Lancet"},{"issue":"6","key":"6821_CR2","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1172\/JCI72271","volume":"124","author":"K Reidy","year":"2014","unstructured":"Reidy K, Kang HM, Hostetter T, Susztak K (2014) Molecular mechanisms of diabetic kidney disease. J Clin Invest 124(6):2333\u201340. https:\/\/doi.org\/10.1172\/JCI72271","journal-title":"J Clin Invest"},{"issue":"2","key":"6821_CR3","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1681\/ASN.0000000000000271","volume":"35","author":"KJ Mayne","year":"2024","unstructured":"Mayne KJ, Staplin N, Keane DF et al (2024) Effects of empagliflozin on fluid overload, weight, and blood pressure in CKD. J Am Soc Nephrol 35(2):202\u2013215. https:\/\/doi.org\/10.1681\/ASN.0000000000000271","journal-title":"J Am Soc Nephrol"},{"issue":"1","key":"6821_CR4","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/nrneph.2011.151","volume":"8","author":"GI Welsh","year":"2011","unstructured":"Welsh GI, Saleem MA (2011) The podocyte cytoskeleton\u2013key to a functioning glomerulus in health and disease. Nat Rev Nephrol 8(1):14\u201321. https:\/\/doi.org\/10.1038\/nrneph.2011.151","journal-title":"Nat Rev Nephrol"},{"issue":"11","key":"6821_CR5","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1007\/s001250051447","volume":"42","author":"TW Meyer","year":"1999","unstructured":"Meyer TW, Bennett PH, Nelson RG (1999) Podocyte number predicts long-term urinary albumin excretion in Pima Indians with type II diabetes and microalbuminuria. Diabetologia 42(11):1341\u20134. https:\/\/doi.org\/10.1007\/s001250051447","journal-title":"Diabetologia"},{"issue":"3","key":"6821_CR6","doi-asserted-by":"publisher","first-page":"755","DOI":"10.2337\/db15-0473","volume":"65","author":"A Tagawa","year":"2016","unstructured":"Tagawa A, Yasuda M, Kume S et al (2016) Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65(3):755\u201367. https:\/\/doi.org\/10.2337\/db15-0473","journal-title":"Diabetes"},{"issue":"3","key":"6821_CR7","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1007\/s00125-025-06612-2","volume":"69","author":"S Matsui","year":"2026","unstructured":"Matsui S, Yamamoto T, Takabatake Y et al (2026) Defective autophagy and AMPK inactivation drive ferroptosis in diabetic kidney disease. Diabetologia 69(3):815\u2013832. https:\/\/doi.org\/10.1007\/s00125-025-06612-2","journal-title":"Diabetologia"},{"issue":"5","key":"6821_CR8","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","volume":"149","author":"SJ Dixon","year":"2012","unstructured":"Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060\u201372. https:\/\/doi.org\/10.1016\/j.cell.2012.03.042","journal-title":"Cell"},{"key":"6821_CR9","doi-asserted-by":"publisher","first-page":"4710","DOI":"10.1016\/j.csbj.2025.10.057","volume":"27","author":"Q Yang","year":"2025","unstructured":"Yang Q, Cai Y, Guan Y et al (2025) Metabolic phenotypes: molecular bridges between health homeostasis and disease imbalance. Comput Struct Biotechnol J 27:4710\u20134719. https:\/\/doi.org\/10.1016\/j.csbj.2025.10.057","journal-title":"Comput Struct Biotechnol J"},{"key":"6821_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-026-02867-9","author":"Q Zhao","year":"2026","unstructured":"Zhao Q, Lu S, Guan Y, Sun Z, Qiu S, Zhang A (2026) Dysregulation of the AMPK-SREBP1-FASN axis in MASLD: driving a vicious cycle of lipotoxicity and metabolic-immune crosstalk. Lipids Health Dis. https:\/\/doi.org\/10.1186\/s12944-026-02867-9","journal-title":"Lipids Health Dis"},{"issue":"3","key":"6821_CR11","doi-asserted-by":"publisher","first-page":"100252","DOI":"10.1016\/j.cellin.2025.100252","volume":"4","author":"S Qiu","year":"2025","unstructured":"Qiu S, Wang Z, Guo S et al (2025) Single cell sequencing and spatial multiomics of diabetic kidney segmentation insights zonation-specific therapeutic metabolic pathways. Cell Insight 4(3):100252. https:\/\/doi.org\/10.1016\/j.cellin.2025.100252","journal-title":"Cell Insight"},{"issue":"1","key":"6821_CR12","doi-asserted-by":"publisher","first-page":"2832","DOI":"10.1038\/s41467-019-10861-2","volume":"10","author":"BB Lake","year":"2019","unstructured":"Lake BB, Chen S, Hoshi M et al (2019) A single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys. Nat Commun 10(1):2832. https:\/\/doi.org\/10.1038\/s41467-019-10861-2","journal-title":"Nat Commun"},{"issue":"5","key":"6821_CR13","doi-asserted-by":"publisher","first-page":"loaf019","DOI":"10.1093\/lifemeta\/loaf019","volume":"4","author":"S Qiu","year":"2025","unstructured":"Qiu S, Xie D, Guo S et al (2025) Spatially segregated multiomics decodes metformin-mediated functional-specific metabolic characteristics in diabetic kidney disease. Life Metab 4(5):loaf019. https:\/\/doi.org\/10.1093\/lifemeta\/loaf019","journal-title":"Life Metab"},{"issue":"3","key":"6821_CR14","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1016\/j.fmre.2026.02.005","volume":"6","author":"S Qiu","year":"2026","unstructured":"Qiu S, Wang Z, Guo S et al (2026) Spatial atlas of human diabetic kidney uncovered podocyte-driven metabolic-inflammatory crosstalk via glycerolipid reprogramming and DUSP4\/MMP3 axis. Fundam Res 6(3):1985\u20131997. https:\/\/doi.org\/10.1016\/j.fmre.2026.02.005","journal-title":"Fundam Res"},{"issue":"1","key":"6821_CR15","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/s41420-026-02990-7","volume":"12","author":"S Qiu","year":"2026","unstructured":"Qiu S, Xie D, Guo S et al (2026) MAPK14\/SLC7A11\/GPX4 axis dysregulation drives podocyte ferroptosis via mediating glycerophospholipid metabolism. Cell Death Discov 12(1):147. https:\/\/doi.org\/10.1038\/s41420-026-02990-7","journal-title":"Cell Death Discov"},{"issue":"10","key":"6821_CR16","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/s41574-019-0242-2","volume":"15","author":"M Foretz","year":"2019","unstructured":"Foretz M, Guigas B, Viollet B (2019) Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 15(10):569\u2013589. https:\/\/doi.org\/10.1038\/s41574-019-0242-2","journal-title":"Nat Rev Endocrinol"},{"issue":"3","key":"6821_CR17","doi-asserted-by":"publisher","first-page":"191","DOI":"10.7326\/M16-1901","volume":"166","author":"MJ Crowley","year":"2017","unstructured":"Crowley MJ, Diamantidis CJ, McDuffie JR et al (2017) Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review. Ann Intern Med 166(3):191\u2013200. https:\/\/doi.org\/10.7326\/M16-1901","journal-title":"Ann Intern Med"},{"issue":"4","key":"6821_CR18","doi-asserted-by":"publisher","first-page":"409","DOI":"10.3390\/antiox15040409","volume":"15","author":"I Lu\u010di\u0107","year":"2026","unstructured":"Lu\u010di\u0107 I, Vojkovi\u0107 M, Milkovi\u0107 L (2026) The AMPK\/NRF2\/FOXO axis in CKD-molecular and clinical perspectives. Antioxidants (Basel) 15(4):409. https:\/\/doi.org\/10.3390\/antiox15040409","journal-title":"Antioxidants (Basel)"},{"issue":"7506","key":"6821_CR19","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/nature13270","volume":"510","author":"AK Madiraju","year":"2014","unstructured":"Madiraju AK, Erion DM, Rahimi Y et al (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510(7506):542\u20136. https:\/\/doi.org\/10.1038\/nature13270","journal-title":"Nature"},{"issue":"2","key":"6821_CR20","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/s41556-020-0461-8","volume":"22","author":"H Lee","year":"2020","unstructured":"Lee H, Zandkarimi F, Zhang Y et al (2020) Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol 22(2):225\u2013234. https:\/\/doi.org\/10.1038\/s41556-020-0461-8","journal-title":"Nat Cell Biol"},{"key":"6821_CR21","doi-asserted-by":"publisher","first-page":"116584","DOI":"10.1016\/j.jpba.2024.116584","volume":"254","author":"J Chai","year":"2025","unstructured":"Chai J, Wang Y, Guo S et al (2025) Proteomics exploration of metformin hydrochloride for diabetic kidney disease treatment via the butanoate metabolism pathway. J Pharm Biomed Anal 254:116584. https:\/\/doi.org\/10.1016\/j.jpba.2024.116584","journal-title":"J Pharm Biomed Anal"},{"key":"6821_CR22","doi-asserted-by":"publisher","first-page":"231825","DOI":"10.1155\/2015\/231825","volume":"2015","author":"L Zhai","year":"2015","unstructured":"Zhai L, Gu J, Yang D, Wang W, Ye S (2015) Metformin ameliorates podocyte damage by restoring renal tissue podocalyxin expression in type 2 diabetic rats. J Diabetes Res 2015:231825. https:\/\/doi.org\/10.1155\/2015\/231825","journal-title":"J Diabetes Res"},{"key":"6821_CR23","doi-asserted-by":"publisher","first-page":"210821","DOI":"10.1155\/2012\/210821","volume":"2012","author":"J Kim","year":"2012","unstructured":"Kim J, Shon E, Kim CS, Kim JS (2012) Renal podocyte injury in a rat model of type 2 diabetes is prevented by metformin. Exp Diabetes Res 2012:210821. https:\/\/doi.org\/10.1155\/2012\/210821","journal-title":"Exp Diabetes Res"},{"issue":"1","key":"6821_CR24","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/nep.14121","volume":"28","author":"LP Kolligundla","year":"2023","unstructured":"Kolligundla LP, Kavvuri R, Singh AK, Mukhi D, Pasupulati AK (2023) Metformin prevents hypoxia-induced podocyte injury by regulating the ZEB2\/TG2 axis. Nephrology (Carlton) 28(1):60\u201371. https:\/\/doi.org\/10.1111\/nep.14121","journal-title":"Nephrology (Carlton)"},{"issue":"1","key":"6821_CR25","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/s43856-025-01152-7","volume":"5","author":"D Xie","year":"2025","unstructured":"Xie D, Zhu Y, Guo S et al (2025) The metformin mediated MAPK signaling pathway influences D-Xylose regulation during diabetic kidney disease therapy. Commun Med (Lond) 5(1):454. https:\/\/doi.org\/10.1038\/s43856-025-01152-7","journal-title":"Commun Med (Lond)"},{"issue":"43","key":"6821_CR26","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2006","unstructured":"Subramanian A, Tamayo P, Mootha VK et al (2006) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545\u201315550. https:\/\/doi.org\/10.1073\/pnas.0506580102","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"6821_CR27","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/ng1180","volume":"34","author":"VK Mootha","year":"2003","unstructured":"Mootha VK, Lindgren CM, Eriksson K-F et al (2003) PGC-1-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267\u2013273. https:\/\/doi.org\/10.1038\/ng1180","journal-title":"Nat Genet"},{"issue":"11","key":"6821_CR28","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1002\/2211-5463.70061","volume":"15","author":"SS Zadian","year":"2025","unstructured":"Zadian SS, Jahanbin K, Nikooei S et al (2025) Current trends in single-cell RNA sequencing applications in diabetes mellitus. FEBS Open Bio 15(11):1738\u20131761. https:\/\/doi.org\/10.1002\/2211-5463.70061","journal-title":"FEBS Open Bio"},{"key":"6821_CR29","doi-asserted-by":"publisher","first-page":"1700004","DOI":"10.3389\/fimmu.2025.1700004","volume":"16","author":"Y Luo","year":"2025","unstructured":"Luo Y, Long M, Wu X, Zeng L (2025) Targeting ferroptosis: novel therapeutic approaches and intervention strategies for kidney diseases. Front Immunol 16:1700004. https:\/\/doi.org\/10.3389\/fimmu.2025.1700004","journal-title":"Front Immunol"},{"issue":"6","key":"6821_CR30","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1038\/s41589-022-01249-3","volume":"19","author":"AN von Krusenstiern","year":"2023","unstructured":"von Krusenstiern AN, Robson RN, Qian N et al (2023) Identification of essential sites of lipid peroxidation in ferroptosis. Nat Chem Biol 19(6):719\u2013730. https:\/\/doi.org\/10.1038\/s41589-022-01249-3","journal-title":"Nat Chem Biol"},{"issue":"1","key":"6821_CR31","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nchembio.2238","volume":"13","author":"VE Kagan","year":"2017","unstructured":"Kagan VE, Mao G, Qu F et al (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81\u201390. https:\/\/doi.org\/10.1038\/nchembio.2238","journal-title":"Nat Chem Biol"},{"key":"6821_CR32","doi-asserted-by":"publisher","first-page":"123411","DOI":"10.1016\/j.lfs.2025.123411","volume":"363","author":"Q Yang","year":"2025","unstructured":"Yang Q, Cai Y, Wang Z, Guo S, Qiu S, Zhang A (2025) Understanding the physiological mechanisms and therapeutic targets of diseases: lipidomics strategies. Life Sci 363:123411. https:\/\/doi.org\/10.1016\/j.lfs.2025.123411","journal-title":"Life Sci"},{"issue":"12","key":"6821_CR33","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1007\/s00018-019-03294-z","volume":"77","author":"A Christofides","year":"2020","unstructured":"Christofides A, Papagregoriou G, Dweep H et al (2020) Evidence for miR-548c-5p regulation of FOXC2 transcription through a distal genomic target site in human podocytes. Cell Mol Life Sci 77(12):2441\u20132459. https:\/\/doi.org\/10.1007\/s00018-019-03294-z","journal-title":"Cell Mol Life Sci"},{"issue":"10","key":"6821_CR34","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1038\/nmeth.4407","volume":"14","author":"N Habib","year":"2017","unstructured":"Habib N, Avraham-Davidi I, Basu A et al (2017) Massively parallel single-nucleus RNA-seq with DroNc-seq. Nat Methods 14(10):955\u2013958. https:\/\/doi.org\/10.1038\/nmeth.4407","journal-title":"Nat Methods"},{"issue":"1","key":"6821_CR35","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1038\/s41467-021-22266-1","volume":"12","author":"Z Miao","year":"2021","unstructured":"Miao Z, Balzer MS, Ma Z et al (2021) Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets. Nat Commun 12(1):2277. https:\/\/doi.org\/10.1038\/s41467-021-22266-1","journal-title":"Nat Commun"},{"key":"6821_CR36","doi-asserted-by":"publisher","first-page":"4473803","DOI":"10.1155\/ije\/4473803","volume":"2025","author":"S Xue","year":"2025","unstructured":"Xue S, Fan W, Li Q, Huang H, Tang Y, Wu M (2025) Puerarin attenuates podocyte damage in mice with diabetic kidney disease by modulating the AMPK\/Nrf2 pathway. Int J Endocrinol 2025:4473803. https:\/\/doi.org\/10.1155\/ije\/4473803","journal-title":"Int J Endocrinol"},{"issue":"2","key":"6821_CR37","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1681\/ASN.2006060604","volume":"18","author":"FY Ma","year":"2007","unstructured":"Ma FY, Flanc RS, Tesch GH et al (2007) A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol 18(2):472\u201384. https:\/\/doi.org\/10.1681\/ASN.2006060604","journal-title":"J Am Soc Nephrol"},{"key":"6821_CR38","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/j.jare.2024.04.012","volume":"69","author":"Z Zou","year":"2025","unstructured":"Zou Z, Hu W, Kang F et al (2025) Interplay between lipid dysregulation and ferroptosis in chondrocytes and the targeted therapy effect of metformin on osteoarthritis. J Adv Res 69:515\u2013529. https:\/\/doi.org\/10.1016\/j.jare.2024.04.012","journal-title":"J Adv Res"},{"issue":"2","key":"6821_CR39","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/s41419-020-2298-2","volume":"11","author":"J Li","year":"2020","unstructured":"Li J, Cao F, Yin HL et al (2020) Ferroptosis: past, present and future. Cell Death Dis 11(2):88. https:\/\/doi.org\/10.1038\/s41419-020-2298-2","journal-title":"Cell Death Dis"},{"key":"6821_CR40","unstructured":"ClinicalTrials.gov. Effect of metformin on podocyte injury in focal segmental glomerulosclerosis. NCT06090227. https:\/\/clinicaltrials.gov\/study\/NCT06090227"},{"key":"6821_CR41","doi-asserted-by":"publisher","first-page":"113467","DOI":"10.1016\/j.ecoenv.2022.113467","volume":"236","author":"C Huang","year":"2022","unstructured":"Huang C, Wu D, Zhang K et al (2022) Perfluorooctanoic acid alters the developmental trajectory of female germ cells and embryos in rodents and its potential mechanism. Ecotoxicol Environ Saf 236:113467. https:\/\/doi.org\/10.1016\/j.ecoenv.2022.113467","journal-title":"Ecotoxicol Environ Saf"},{"issue":"1","key":"6821_CR42","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1186\/s12934-024-02593-w","volume":"23","author":"J Wang","year":"2024","unstructured":"Wang J, Chen Y, Cong J, Wang W (2024) Metformin regulates cellulase production in Trichoderma reesei via calcium signaling and mitochondrial function. Microb Cell Fact 23(1):314. https:\/\/doi.org\/10.1186\/s12934-024-02593-w","journal-title":"Microb Cell Fact"},{"issue":"1","key":"6821_CR43","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/ki.2014.128","volume":"87","author":"ME Molitch","year":"2015","unstructured":"Molitch ME, Adler AI, Flyvbjerg A et al (2015) Diabetic kidney disease: a clinical update from kidney disease: improving global outcomes. Kidney Int 87(1):20\u201330. https:\/\/doi.org\/10.1038\/ki.2014.128","journal-title":"Kidney Int"},{"issue":"4","key":"6821_CR44","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s40265-026-02286-1","volume":"86","author":"L Del Vecchio","year":"2026","unstructured":"Del Vecchio L, Fernandez-Fernandez B, Fornoni A, Kronbichler A, Ortiz A (2026) More than glucose elimination: additional benefits of SGLT2 inhibitors in glomerular diseases. Drugs 86(4):429\u2013442. https:\/\/doi.org\/10.1007\/s40265-026-02286-1","journal-title":"Drugs"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06821-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06821-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06821-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:39:21Z","timestamp":1790771961000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06821-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":44,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["6821"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06821-3","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]},"assertion":[{"value":"7 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors wish to thank Shanghai OE Biotech for their technical assistance.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The data that support the findings are included within the ESM.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors are grateful for the generous support from the Program of Natural Science Foundation of State (grant no. 82560836, 81973745, 82104733), Hainan Provincial Natural Science Foundation of China (826JCQN0974), Hainan Province Nanhai New Star Science and Technology Innovation Talent Platform Project by Hainan Provincial Department of Science and Technology (NHXXRCXM202317), and Academic Enhancement Support Program by Hainan Medical University (XSTS2026035, XSTS2025079).","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"SQ, ST, WS, YX and AZ conceived and designed the study. DX, SG, ZW and YC performed the animal experiments, MALDI-MSI acquisition, in vitro podocyte cultures, western blotting, lipid peroxidation assays and clinical sample collection. SQ, YW, XY, YG, QZ and QY conducted the bioinformatic and statistical analyses, and SQ additionally processed the spatial metabolomics data and carried out the snRNA sequencing analysis. SQ drafted the manuscript. ST, WS, YX and AZ critically revised it for important intellectual content. All authors contributed to data interpretation and evaluation, contributed to the editing of the report, and approved the final submitted version of the manuscript. AZ verified the data and had access to raw data. AZ is the guarantor of the integrity of the work as a whole.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}