{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:33:55Z","timestamp":1790192035454,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T00:00:00Z","timestamp":1649203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The latest progress in the field of renal fibrosis mainly focuses on the new concept of \u201cpartial epithelial-mesenchymal transition (pEMT)\u201d to explain the contribution of renal tubular epithelial (RTE) cells to renal fibrosis and the crucial role of fatty acid oxidation (FAO) dysfunction in RTE cells for the development of renal fibrosis. FAO depression is considered to be secondary or occur simultaneously with pEMT. We explored the relationship between pEMT and FAO and the effect of rhein on them. Intragastric administration of rhein significantly improved the levels of BUN, Scr, \u03b1-SMA, collagen 1A and histopathological changes in UUO-rats. Transcriptomic and metabolomic analyses revealed that abnormal signaling pathways were involved in EMT and FAO disorders. RTE cell experiments showed that TGF-\u03b2 could inhibit the activity of Cpt1a, resulting in ATP depletion and lipid deposition. Cpt1a inhibitor induced EMT, while Cpt1 substrate or rhein inhibited EMT, indicating that Cpt1a-mediated FAO dysfunction is essential for RTE cells EMT. Further studies showed that Cpt1a activity were regulated by SirT1\/STAT3\/Twist1 pathway. Rhein inhibits RTE cell EMT by promoting Cpt1a-mediated FAO through the SirT1\/STAT3\/Twist1 pathway. Surprisingly and importantly, our experiments showed that FAO depression occurs before EMT, and EMT is one of the results of FAO depression.<\/jats:p>","DOI":"10.3390\/molecules27072344","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T21:08:22Z","timestamp":1649365702000},"page":"2344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Rhein Improves Renal Fibrosis by Restoring Cpt1a-Mediated Fatty Acid Oxidation through SirT1\/STAT3\/twist1 Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Xianrui","family":"Song","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zesen","family":"Du","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenqi","family":"Yao","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mian","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1681\/ASN.2016050562","article-title":"Global cardiovascular and renal outcomes of reduced GFR","volume":"28","author":"Thomas","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00467-011-1992-9","article-title":"Tubulointerstitial injury and the progression of chronic kidney disease","volume":"27","author":"Hodgkins","year":"2012","journal-title":"Pediatr. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"i89","DOI":"10.1093\/ndt\/gfw388","article-title":"What can target kidney fibrosis?","volume":"32","author":"Leaf","year":"2017","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.kint.2017.09.033","article-title":"Renal tubule injury: A driving force toward chronic kidney disease","volume":"93","author":"Liu","year":"2018","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"593","DOI":"10.2215\/CJN.04980515","article-title":"Prognostic value of tubulointerstitial lesions, urinary N-acetyl-\u03b2-d-glucosaminidase, and urinary \u03b22-microglobulin in patients with type 2 diabetes and biopsy-proven diabetic nephropathy","volume":"11","author":"Mise","year":"2016","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.matbio.2018.02.006","article-title":"Renal fibrosis: Primacy of the proximal tubule","volume":"68","author":"Gewin","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1038\/nm.3902","article-title":"Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis","volume":"21","author":"Lovisa","year":"2015","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1007\/s11255-020-02739-w","article-title":"Rhein protects 5\/6 nephrecto-mized rat against renal injury by reducing inflammation via NF-\u03baB signaling","volume":"53","author":"Liu","year":"2021","journal-title":"Int. Urol. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"737570","DOI":"10.3389\/fphar.2021.737570","article-title":"Epithelial-to-mesenchymal transition in fibrosis: Concepts and targeting strategies","volume":"12","author":"Lovisa","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nm.3762","article-title":"Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development","volume":"21","author":"Kang","year":"2015","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e140695","DOI":"10.1172\/JCI140695","article-title":"Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis","volume":"131","author":"Miguel","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s13020-020-00370-6","article-title":"What we already know about rhubarb: A comprehensive review","volume":"15","author":"Xiang","year":"2020","journal-title":"Chin. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1248\/bpb.b12-00107","article-title":"Rhein inhibits integrin-linked kinase expression and regulates matrix metalloproteinase-9\/tissue inhibitor of metalloproteinase-1 ratio in high glucose-induced epithelial-mesenchymal transition of renal tubular cell","volume":"35","author":"Peng","year":"2012","journal-title":"Biol. Pharm. Bull."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1248\/bpb.34.1219","article-title":"Preventive effects and mechanisms of rhein on renal interstitial fibrosis in obstructive nephropathy","volume":"34","author":"He","year":"2011","journal-title":"Biol. Pharm. Bull."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.3389\/fphar.2019.01473","article-title":"A significant association between rhein and diabetic nephropathy in animals: A systematic review and meta-analysis","volume":"10","author":"Hu","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s40659-019-0257-0","article-title":"Rhein alleviates renal interstitial fibrosis by inhibiting tubular cell apoptosis in rats","volume":"52","author":"Chen","year":"2019","journal-title":"Biol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1369\/0022155419852932","article-title":"Renal inflammation and fibrosis: A double-edged sword","volume":"67","author":"Black","year":"2019","journal-title":"J. Histochem. Cytochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"569322","DOI":"10.3389\/fphys.2020.569322","article-title":"New insights into the role and mechanism of partial epithelial-mesenchymal transition in kidney fibrosis","volume":"11","author":"Sheng","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4179","DOI":"10.1007\/s00018-019-03212-3","article-title":"Molecular determinants of mesenchymal cell activation in fibroproliferative diseases","volume":"76","author":"Penke","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.3390\/ijms16022320","article-title":"Cyclic nucleotide signaling in kidney fibrosis","volume":"16","author":"Schinner","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/cr.2011.144","article-title":"Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms","volume":"22","author":"Qin","year":"2012","journal-title":"Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1159\/000498965","article-title":"Involvement of STAT3 signaling in high glucose-induced epithelial mesenchymal transition in human peritoneal mesothelial cell line HMrSV5","volume":"44","author":"Zhang","year":"2019","journal-title":"Kidney Blood Press. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ncb1857","article-title":"STAT3 inhibition of gluconeogenesis is downregulated by SirT1","volume":"11","author":"Nie","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3389\/fphar.2016.00247","article-title":"A comprehensive and system review for the pharmacological mechanism of action of rhein, an active anthraquinone ingredient","volume":"7","author":"Sun","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1136\/annrheumdis-2015-208470","article-title":"Composition of Twist1 dimers regulates fibroblast activation and tissue fibrosis","volume":"76","author":"Soare","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaaz2597","DOI":"10.1126\/scisignal.aaz2597","article-title":"Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis","volume":"13","author":"Lovisa","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1038\/nm.3901","article-title":"Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease","volume":"21","author":"Grande","year":"2015","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3389\/fmed.2015.00052","article-title":"Alteration of fatty acid oxidation in tubular epithelial cells: From acute kidney injury to renal fibrogenesis","volume":"2","author":"Simon","year":"2015","journal-title":"Front. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.tem.2016.06.004","article-title":"Partial epithelial-to-mesenchymal transition and other new mechanisms of kidney fibrosis","volume":"27","author":"Lovisa","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3389\/fendo.2012.00108","article-title":"A tale with a Twist: A developmental gene with potential relevance for metabolic dysfunction and inflammation in adipose tissue","volume":"3","author":"Dobrian","year":"2012","journal-title":"Front. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.canlet.2013.04.024","article-title":"STAT3 mediates TGF-\u03b21-induced Twist1 expression and prostate cancer invasion","volume":"336","author":"Cho","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.4155\/fmc-2019-0153","article-title":"Management of diabetic nephropathy: The role of sirtuin-1","volume":"11","author":"Wang","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Otsuki, M., Fukuda, N., Inoue, T., Mineshige, T., Otsuki, T., Horikoshi, S., Endo, M., and Abe, M. (2019). Preclinical study of DNA-recognized peptide compound pyrrole-imidazole polyamide targeting human TGF-\u03b21 promoter for progressive renal diseases in the common marmoset. Molecules, 24.","DOI":"10.20944\/preprints201908.0090.v1"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113212","DOI":"10.1016\/j.jep.2020.113212","article-title":"Effects of Acanthopanax senticosus (Rupr. & Maxim.) Harms on cerebral ischemia-reperfusion injury revealed by metabolomics and transcriptomics","volume":"264","author":"Chen","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_35","unstructured":"Zalups, R.K., and Lash, L.H. (1996). Methods in Renal Toxicology, CRC Press."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/7\/2344\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:48:57Z","timestamp":1760136537000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/7\/2344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,6]]},"references-count":35,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["molecules27072344"],"URL":"https:\/\/doi.org\/10.3390\/molecules27072344","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,6]]}}}