{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T04:57:15Z","timestamp":1790571435162,"version":"4.1.0"},"reference-count":50,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2027,2,1]],"date-time":"2027-02-01T00:00:00Z","timestamp":1801440000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2027,2,1]],"date-time":"2027-02-01T00:00:00Z","timestamp":1801440000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2027,2,1]],"date-time":"2027-02-01T00:00:00Z","timestamp":1801440000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2027,2,1]],"date-time":"2027-02-01T00:00:00Z","timestamp":1801440000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2027,2,1]],"date-time":"2027-02-01T00:00:00Z","timestamp":1801440000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2027,2,1]],"date-time":"2027-02-01T00:00:00Z","timestamp":1801440000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2027,2,1]],"date-time":"2027-02-01T00:00:00Z","timestamp":1801440000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274476"],"award-info":[{"award-number":["82274476"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Ethnopharmacology"],"published-print":{"date-parts":[[2027,2]]},"DOI":"10.1016\/j.jep.2026.122363","type":"journal-article","created":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T06:30:43Z","timestamp":1788589843000},"page":"122363","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"P1","title":["Effects of Heidihuang Pill on renal fibrosis and senescence-associated changes in rats with unilateral ureteral obstruction: A fecal metabolomics and Klotho-knockdown study"],"prefix":"10.1016","volume":"374","author":[{"given":"Guannan","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamin","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenping","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"8","key":"10.1016\/j.jep.2026.122363_bib1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpha.2024.01.001","article-title":"Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis","volume":"14","author":"Bao","year":"2024","journal-title":"J. Pharm. Anal."},{"issue":"Pt 2","key":"10.1016\/j.jep.2026.122363_bib2","article-title":"Phytochemical component profiling and anti-renal fibrosis effects of crude and salt-stir fried Eucommiae Cortex extracts on renal fibrosis rats caused by high-purine diet","volume":"464","author":"Cai","year":"2025","journal-title":"Food Chem."},{"issue":"3","key":"10.1016\/j.jep.2026.122363_bib3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0234-2","article-title":"Unilateral ureteral obstruction causes gut microbial dysbiosis and metabolome disorders contributing to tubulointerstitial fibrosis","volume":"51","author":"Chen","year":"2019","journal-title":"Exp. Mol. Med."},{"issue":"3","key":"10.1016\/j.jep.2026.122363_bib4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0234-2","article-title":"Unilateral ureteral obstruction causes gut microbial dysbiosis and metabolome disorders contributing to tubulointerstitial fibrosis","volume":"51","author":"Chen","year":"2019","journal-title":"Exp. Mol. Med."},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib5","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/s41392-025-02532-0","article-title":"Decoding organ fibrosis: mechanistic insights and emerging therapeutic strategies","volume":"11","author":"Chen","year":"2026","journal-title":"Signal Transduct. Targeted Ther."},{"issue":"11","key":"10.1016\/j.jep.2026.122363_bib6","doi-asserted-by":"crossref","first-page":"439","DOI":"10.3390\/cancers10110439","article-title":"The role of the anti-aging protein klotho in IGF-1 signaling and reticular calcium leak: impact on the chemosensitivity of dedifferentiated liposarcomas","volume":"10","author":"Delcroix","year":"2018","journal-title":"Cancers"},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib7","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1186\/s12951-025-03499-4","article-title":"The effects of Klotho delivering mesenchymal stem cell-derived small extracellular vesicles on acute kidney injury","volume":"23","author":"Deng","year":"2025","journal-title":"J. Nanobiotechnol."},{"issue":"Pt B","key":"10.1016\/j.jep.2026.122363_bib8","article-title":"Yishen Qufeng formula mediates ferroptosis to improve renal fibrosis in unilateral ureteral obstruction rats","volume":"353","author":"Gao","year":"2025","journal-title":"J. Ethnopharmacol."},{"issue":"21","key":"10.1016\/j.jep.2026.122363_bib9","doi-asserted-by":"crossref","first-page":"3443","DOI":"10.3390\/cells11213443","article-title":"Cellular senescence in metabolic-associated kidney disease: an update","volume":"11","author":"Gao","year":"2022","journal-title":"Cells"},{"issue":"10518","key":"10.1016\/j.jep.2026.122363_bib10","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1016\/S0140-6736(25)01853-7","article-title":"Global, regional, and national burden of chronic kidney disease in adults, 1990-2023, and its attributable risk factors: a systematic analysis for the global Burden of disease study 2023","volume":"406","year":"2025","journal-title":"Lancet (London, England)"},{"issue":"4","key":"10.1016\/j.jep.2026.122363_bib11","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1111\/cen.14380","article-title":"Klotho gene G395A and C1818T polymorphisms in acromegaly: association with clinical presentation and comorbidities","volume":"94","author":"Helvaci","year":"2021","journal-title":"Clin. Endocrinol."},{"key":"10.1016\/j.jep.2026.122363_bib12","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejphar.2020.173555","article-title":"Longitudinal analysis of fecal microbiome and metabolome during renal fibrotic progression in a unilateral ureteral obstruction animal model","volume":"886","author":"Hu","year":"2020","journal-title":"Eur. J. Pharmacol."},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/s41392-023-01379-7","article-title":"Kidney fibrosis: from mechanisms to therapeutic medicines","volume":"8","author":"Huang","year":"2023","journal-title":"Signal Transduct. Targeted Ther."},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41536-024-00348-0","article-title":"Engineered extracellular vesicle-encapsulated CHIP as novel nanotherapeutics for treatment of renal fibrosis","volume":"9","author":"Ji","year":"2024","journal-title":"npj Regen. Med."},{"issue":"3","key":"10.1016\/j.jep.2026.122363_bib15","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1161\/HYPERTENSIONAHA.120.16635","article-title":"Role of Klotho in the development of essential hypertension","volume":"77","author":"Kanbay","year":"2021","journal-title":"Hypertension (Dallas, Tex. : 1979)"},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2024.108047","article-title":"The signaling landscape of insulin-like growth factor 1","volume":"301","author":"Khan","year":"2025","journal-title":"J. Biol. Chem."},{"issue":"8","key":"10.1016\/j.jep.2026.122363_bib17","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1681\/ASN.2020091373","article-title":"Progressive cellular senescence mediates renal dysfunction in ischemic nephropathy","volume":"32","author":"Kim","year":"2021","journal-title":"J. Am. Soc. Nephrol. : JASN"},{"key":"10.1016\/j.jep.2026.122363_bib18","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2020.153274","article-title":"Uncovering the mechanism of Astragali Radix against nephrotic syndrome by intergrating lipidomics and network pharmacology","volume":"77","author":"Li","year":"2020","journal-title":"Phytomedicine : Int. J. Phytother. Phytopharmacol."},{"key":"10.1016\/j.jep.2026.122363_bib19","doi-asserted-by":"crossref","DOI":"10.1016\/j.biomaterials.2024.122926","article-title":"Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPAR\u03b1 signaling in renal tubular epithelial cells","volume":"315","author":"Li","year":"2025","journal-title":"Biomaterials"},{"key":"10.1016\/j.jep.2026.122363_bib20","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.jare.2025.07.015","article-title":"Direct pharmacological targeting of Piezo1 by Paeoniflorin: a novel therapeutic approach for renal fibrosis","volume":"82","author":"Li","year":"2026","journal-title":"J. Adv. Res."},{"key":"10.1016\/j.jep.2026.122363_bib21","article-title":"Heidihuangwan alleviates renal fibrosis in rats with 5\/6 nephrectomy by inhibiting autophagy","volume":"13","author":"Li","year":"2022","journal-title":"Front. Pharmacol."},{"issue":"Pt A","key":"10.1016\/j.jep.2026.122363_bib22","article-title":"Anti-apoptotic effect of HeidihuangWan in renal tubular epithelial cells via PI3K\/Akt\/mTOR signaling pathway","volume":"302","author":"Li","year":"2023","journal-title":"J. Ethnopharmacol."},{"issue":"20","key":"10.1016\/j.jep.2026.122363_bib23","article-title":"Multimodal AI-Driven identification of Dehydrocostus Lactone as a potent renal fibrosis attenuator targeting IQGAP1","volume":"13","author":"Lin","year":"2026","journal-title":"Adv. Sci. (Weinheim, Baden-Wurttemberg, Germany)"},{"issue":"11","key":"10.1016\/j.jep.2026.122363_bib24","doi-asserted-by":"crossref","first-page":"5085","DOI":"10.1002\/ptr.70091","article-title":"Artesunate enhances DUSP1-Dependent mitochondrial integrity to mitigate renal fibrosis in diabetic kidney disease","volume":"39","author":"Liu","year":"2025","journal-title":"Phytother Res. : PTR"},{"issue":"9","key":"10.1016\/j.jep.2026.122363_bib25","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1021\/acs.orglett.5c00317","article-title":"Triangesinenolides A-C: trimeric phthalides with anti-renal fibrosis potential from Angelica sinensis","volume":"27","author":"Lv","year":"2025","journal-title":"Org. Lett."},{"issue":"8","key":"10.1016\/j.jep.2026.122363_bib26","first-page":"1337","article-title":"An analysis of the relationships between serum complement C3, hyaluronic acid and IL-6 and type 2 diabetic nephropathy","volume":"27","author":"Mao","year":"2020","journal-title":"Labeled Immunoassays Clin.Med."},{"issue":"2","key":"10.1016\/j.jep.2026.122363_bib27","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1159\/000086500","article-title":"Oxidative stress decreases klotho expression in a mouse kidney cell line","volume":"101","author":"Mitobe","year":"2005","journal-title":"Nephron Exp. Nephrol."},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib28","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bbrc.2011.02.089","article-title":"Overexpression of klotho protein modulates uninephrectomy-induced compensatory renal hypertrophy by suppressing IGF-I signals","volume":"407","author":"Nagasu","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.jep.2026.122363_bib29","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2025.157121","article-title":"Integrated bioinformatics and multi-omics reveal Astragalus extract's gut-kidney axis mechanism in hyperuricemic nephropathy via purine metabolism","volume":"146","author":"Qu","year":"2025","journal-title":"Phytomedicine : Int. J. Phytother. Phytopharmacol."},{"issue":"4","key":"10.1016\/j.jep.2026.122363_bib30","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/2211-5463.12202","article-title":"Inhibition of the TGF\u03b2 signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis","volume":"7","author":"Schinner","year":"2017","journal-title":"FEBS Open Bio"},{"issue":"4","key":"10.1016\/j.jep.2026.122363_bib31","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/2211-5463.12202","article-title":"Inhibition of the TGF\u03b2 signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis","volume":"7","author":"Schinner","year":"2017","journal-title":"FEBS Open Bio"},{"issue":"20","key":"10.1016\/j.jep.2026.122363_bib32","doi-asserted-by":"crossref","DOI":"10.1172\/JCI170341","article-title":"Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients","volume":"133","author":"Sharma","year":"2023","journal-title":"J. Clin. Investig."},{"issue":"4","key":"10.1016\/j.jep.2026.122363_bib33","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1159\/000324885","article-title":"Indoxyl sulfate downregulates renal expression of Klotho through production of ROS and activation of nuclear factor-\u0138B","volume":"33","author":"Shimizu","year":"2011","journal-title":"Am. J. Nephrol."},{"issue":"4","key":"10.1016\/j.jep.2026.122363_bib34","first-page":"132","article-title":"Study on the intervention mechanism of Heidihuang Pill in regulating lipid metabolism disorder and improving \"Micro-inflammatory State\" in patients with chronic renal failure","volume":"19","author":"Sun","year":"2017","journal-title":"J. Liaoning Univ. Trad. Chin. Med."},{"issue":"3","key":"10.1016\/j.jep.2026.122363_bib35","doi-asserted-by":"crossref","DOI":"10.1111\/cts.13770","article-title":"Natural intestinal metabolite xylitol reduces BRD4 levels to mitigate renal fibrosis","volume":"17","author":"Tan","year":"2024","journal-title":"Clin. Transl. Sci."},{"key":"10.1016\/j.jep.2026.122363_bib36","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2025.1664254","article-title":"Exploring the mechanism of Heidihuang Pill in the treatment of osteoporosis based on network pharmacology, molecular docking, and experimental validation","volume":"16","author":"Tian","year":"2025","journal-title":"Front Endocrinol (Lausanne)"},{"key":"10.1016\/j.jep.2026.122363_bib37","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2024.155991","article-title":"Astragaloside IV attenuates fatty acid-induced renal tubular injury in diabetic kidney disease by inhibiting fatty acid transport protein-2","volume":"134","author":"Wang","year":"2024","journal-title":"Phytomedicine : Int. J. Phytother. Phytopharmacol."},{"key":"10.1016\/j.jep.2026.122363_bib38","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2024.156351","article-title":"Sang-Bai-Pi extract and its constituent regiafuran C ameliorate renal fibrosis through TGF-\u03b2\/Smad and Wnt\/\u03b2-catenin signaling pathways","volume":"136","author":"Wei","year":"2025","journal-title":"Phytomedicine : Int. J. Phytother. Phytopharmacol."},{"issue":"10","key":"10.1016\/j.jep.2026.122363_bib39","first-page":"1260","article-title":"Research progress of Black Rehmannia Pill on chronic renal failure","volume":"23","author":"Wu","year":"2024","journal-title":"Chin. J. Difficult and Complicated Cases"},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib40","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41538-025-00654-x","article-title":"Haematococcus pluvialis ameliorates renal fibrosis by restoring mitophagy via PINK1-Parkin-p62-LC3 signaling","volume":"10","author":"Wu","year":"2025","journal-title":"npj Sci. Food"},{"key":"10.1016\/j.jep.2026.122363_bib41","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2026.158049","article-title":"Asiaticoside attenuates renal fibrosis by targeting STAT3 to restore Th17\/Treg homeostasis","volume":"155","author":"Xie","year":"2026","journal-title":"Phytomedicine : Int. J. Phytother. Phytopharmacol."},{"key":"10.1016\/j.jep.2026.122363_bib42","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2025.156426","article-title":"Chaihuang Yishen Granule ameliorates mitochondrial homeostasis by upregulating PRDX5\/TFAM axis to inhibit renal fibrosis in CKD","volume":"139","author":"Xu","year":"2025","journal-title":"Phytomedicine : Int. J. Phytother. Phytopharmacol."},{"issue":"9","key":"10.1016\/j.jep.2026.122363_bib43","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41581-024-00868-4","article-title":"Pathological mechanisms of kidney disease in ageing","volume":"20","author":"Yamamoto","year":"2024","journal-title":"Nat. Rev. Nephrol."},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib44","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/s41420-025-02739-8","article-title":"Exosomal miR-122-5p from tubular cells ameliorates renal interstitial fibrosis by regulating fibroblasts via HIF-1\u03b1","volume":"11","author":"Yang","year":"2025","journal-title":"Cell Death Discov."},{"issue":"3","key":"10.1016\/j.jep.2026.122363_bib45","first-page":"788","article-title":"Inhibitory effect of Heidihuang Pills on renal fibrosis in a rat model of chronic renal failure via regulation of IGF-1 expression","volume":"46","author":"Ye","year":"2024","journal-title":"Chin. Tradit. Pat. Med."},{"issue":"1","key":"10.1016\/j.jep.2026.122363_bib46","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s43556-026-00555-9","article-title":"Twist family BHLH transcription factor 1 orchestrates hypoxia-lactate crosstalk to bridge glycolytic flux and tubular maladaptation in fibrotic kidneys","volume":"7","author":"Yu","year":"2026","journal-title":"Mol Biomed"},{"issue":"7","key":"10.1016\/j.jep.2026.122363_bib47","first-page":"586","article-title":"Effect of Heidihuang pill on hyporeactivity of erythropoietin in patients with renal anemia","volume":"20","author":"Zhao","year":"2019","journal-title":"Chin. J. Integrated Tradit. Western Nephrol."},{"issue":"9","key":"10.1016\/j.jep.2026.122363_bib48","first-page":"1846","article-title":"Efficacy of Heidihuang pills on renal anemia patients with chronic kidney disease and effect on iron metabolism","author":"Zhao","year":"2024","journal-title":"World J. Integrated Tradi. Western Med. 19"},{"issue":"10","key":"10.1016\/j.jep.2026.122363_bib49","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1038\/s41401-022-00898-3","article-title":"Dihydroartemisinin suppresses renal fibrosis in mice by inhibiting DNA-methyltransferase 1 and increasing Klotho","volume":"43","author":"Zhou","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"10.1016\/j.jep.2026.122363_bib50","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2025.120490","article-title":"Guiqi Yishen granule alleviates obstructive nephropathy-induced renal fibrosis by targeting PI3K\/AKT signaling pathway","volume":"354","author":"Zhu","year":"2026","journal-title":"J. Ethnopharmacol."}],"container-title":["Journal of Ethnopharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0378874126012183?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0378874126012183?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T04:52:16Z","timestamp":1790571136000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0378874126012183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2027,2]]},"references-count":50,"alternative-id":["S0378874126012183"],"URL":"https:\/\/doi.org\/10.1016\/j.jep.2026.122363","relation":{},"ISSN":["0378-8741"],"issn-type":[{"value":"0378-8741","type":"print"}],"subject":[],"published":{"date-parts":[[2027,2]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Effects of Heidihuang Pill on renal fibrosis and senescence-associated changes in rats with unilateral ureteral obstruction: A fecal metabolomics and Klotho-knockdown study","name":"articletitle","label":"Article Title"},{"value":"Journal of Ethnopharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jep.2026.122363","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"122363"}}