{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:51:20Z","timestamp":1789055480319,"version":"build-2803163510"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Renal fibrosis is a common pathological endpoint of chronic kidney disease, characterized by excessive deposition of extracellular matrix and loss of functional nephrons. Emerging evidence highlights that profound metabolic reprogramming is a hallmark and a fundamental driver of renal fibrosis. Alterations in the central metabolic pathways, including glycolysis, mitochondrial dysfunction and lipid metabolism in tubular epithelial cells promote tubular epithelial cell dysfunction and sustain a pro-fibrotic inflammatory microenvironment. Besides, the metabolic microenvironment, particularly characterized by hypoxia and oxidative stress, plays a critical role in the pathogenesis and progression of renal fibrosis, and targeting the metabolic microenvironment has also emerged as a promising anti-fibrotic strategy. In this review, we summarized the current knowledge and explored the potential of targeting metabolic enzymes or signaling pathways involved in key metabolic pathways may represent a promising strategy to attenuate renal fibrosis. Furthermore, we discussed the contribution of the metabolic microenvironment, including hypoxia and oxidative stress, to the pathogenesis of renal fibrosis.<\/jats:p>","DOI":"10.3389\/fcell.2026.1849072","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:34:53Z","timestamp":1782970493000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting tubular epithelial cell metabolism to halt renal fibrosis: current evidence and future directions"],"prefix":"10.3389","volume":"14","author":[{"given":"Wenke","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, the First Affiliated Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.3390\/antiox12051075","article-title":"PGC-1alpha is a master regulator of mitochondrial lifecycle and ROS stress response","volume":"12","author":"Abu Shelbayeh","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"200138","DOI":"10.1016\/j.ctmp.2024.200138","article-title":"Protective effects of naringin on fipronil-induced cardiovascular and renal dysfunctions in rats","volume":"5","author":"Ajibade","year":"2024","journal-title":"Clin. Tradit. Med. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/s41401-021-00660-1","article-title":"Druggability of lipid metabolism modulation against renal fibrosis","volume":"43","author":"Chen","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"B4","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.cmet.2019.08.003","article-title":"Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis","volume":"30","author":"Chung","year":"2019","journal-title":"Cell. Metab."},{"key":"B5","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.freeradbiomed.2022.07.004","article-title":"GPR87 promotes renal tubulointerstitial fibrosis by accelerating glycolysis and mitochondrial injury","volume":"189","author":"Cui","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"120283","DOI":"10.1016\/j.jep.2025.120283","article-title":"Saikosaponin C ameliorates renal injury and fibrosis via suppression of the HK2\/PKM2\/LDHA signaling mediated glycolysis in CKD","volume":"353","author":"Deng","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1683249","DOI":"10.3389\/fimmu.2025.1683249","article-title":"ATF4 promotes renal tubulointerstitial fibrosis through hexokinase II-mediated glycolysis","volume":"16","author":"Feng","year":"2025","journal-title":"Front. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1007\/s11010-025-05465-y","article-title":"Lactylation-mitochondria axis in chronic kidney disease: metabolic reprogramming, epigenetic dysregulation, and therapeutic potential","volume":"481","author":"Gan","year":"2026","journal-title":"Mol. Cell. Biochem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"200245","DOI":"10.1016\/j.ctmp.2025.200245","article-title":"Total Panax notoginseng saponins treats diabetic kidney disease in mice by regulating the TXNIP\/NLRP3 signaling pathway","volume":"6","author":"Gao","year":"2025","journal-title":"Clin. Traditional Med. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"5478708","DOI":"10.1155\/2020\/5478708","article-title":"Oxidative stress in the pathophysiology of kidney disease: implications for noninvasive monitoring and identification of biomarkers","volume":"23","author":"Gyur\u00e1szov\u00e1","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e2414673","DOI":"10.1002\/advs.202414673","article-title":"Autophagy related 5 promotes mitochondrial fission and inflammation via HSP90-HIF-1alpha-Mediated glycolysis in kidney fibrosis","volume":"12","author":"Hu","year":"2025","journal-title":"Adv. Sci. (Weinh)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e2408753","DOI":"10.1002\/advs.202408753","article-title":"Deletion of pyruvate carboxylase in tubular epithelial cell promotes renal fibrosis by regulating SQOR\/cGAS\/STING-Mediated glycolysis","volume":"12","author":"Huang","year":"2025","journal-title":"Adv. Sci. (Weinh)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2668","DOI":"10.1001\/jama.2014.15298","article-title":"Metformin in patients with type 2 diabetes and kidney disease: a systematic review","volume":"312","author":"Inzucchi","year":"2014","journal-title":"JAMA"},{"key":"B15","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.freeradbiomed.2023.09.011","article-title":"cGAS-STING signaling pathway promotes hypoxia-induced renal fibrosis by regulating PFKFB3-mediated glycolysis","volume":"208","author":"Jiang","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"110123","DOI":"10.1016\/j.cellsig.2021.110123","article-title":"Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-beta","volume":"87","author":"Jim\u00e9nez-Uribe","year":"2021","journal-title":"Cell. Signal"},{"key":"B17","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/s41401-020-00518-y","article-title":"Drp1-dependent mitochondrial fission in cardiovascular disease","volume":"42","author":"Jin","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"B18","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.2147\/DDDT.S473178","article-title":"Revisiting niclosamide formulation approaches - a pathway toward drug repositioning","volume":"18","author":"Jug","year":"2024","journal-title":"Drug Des. Devel Ther."},{"key":"B19","doi-asserted-by":"publisher","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":"B20","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1124\/mol.106.027029","article-title":"Hypoxia-inducible factor-1 (HIF-1)","volume":"70","author":"Ke","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.kint.2024.02.025","article-title":"The key role of altered tubule cell lipid metabolism in kidney disease development","volume":"106","author":"Lee","year":"2024","journal-title":"Kidney Int."},{"key":"B22","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1038\/s41419-022-04515-3","article-title":"STAT6 contributes to renal fibrosis by modulating PPARalpha-mediated tubular fatty acid oxidation","volume":"13","author":"Li","year":"2022","journal-title":"Cell. Death Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1016\/j.kint.2023.01.021","article-title":"Proteomic landscape of the extracellular matrix in the fibrotic kidney","volume":"103","author":"Li","year":"","journal-title":"Kidney Int."},{"key":"B24","doi-asserted-by":"publisher","first-page":"102868","DOI":"10.1016\/j.redox.2023.102868","article-title":"Oxidatively stressed extracellular microenvironment drives fibroblast activation and kidney fibrosis","volume":"67","author":"Li","year":"","journal-title":"Redox Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41419-023-05587-5","article-title":"HIF1alpha-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome","volume":"14","author":"Li","year":"","journal-title":"Cell. Death Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1097\/CM9.0000000000003022","article-title":"Role of mitochondrial dysfunction in kidney disease: insights from the cGAS-STING signaling pathway","volume":"137","author":"Li","year":"2024","journal-title":"Chin. Med. J. Engl."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e2505752122","DOI":"10.1073\/pnas.2505752122","article-title":"Tubular ACSM3 deficiency impairs medium-chain fatty acid metabolism and aggravates kidney fibrosis","volume":"122","author":"Li","year":"","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B28","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/j.ymthe.2024.12.053","article-title":"ATGL regulates renal fibrosis by reprogramming lipid metabolism during the transition from AKI to CKD","volume":"33","author":"Li","year":"","journal-title":"Mol. Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1111\/jcmm.13060","article-title":"Signalling pathways involved in hypoxia-induced renal fibrosis","volume":"21","author":"Liu","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1007\/s00018-020-03645-1","article-title":"Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation","volume":"78","author":"Liu","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3758","DOI":"10.7150\/thno.71722","article-title":"Twist1 downregulation of PGC-1alpha decreases fatty acid oxidation in tubular epithelial cells, leading to kidney fibrosis","volume":"12","author":"Liu","year":"2022","journal-title":"Theranostics"},{"key":"B34","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1038\/s41556-024-01419-6","article-title":"TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA","volume":"26","author":"Liu","year":"2024","journal-title":"Nat. Cell. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1080\/15548627.2025.2581212","article-title":"CircAASS alleviates renal injury and fibrosis by regulating mitochondrial homeostasis in tubular epithelial cells","volume":"22","author":"Ma","year":"2026","journal-title":"Autophagy"},{"key":"B36","doi-asserted-by":"publisher","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":"B37","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/s41581-024-00889-z","article-title":"Metabolism at the crossroads of inflammation and fibrosis in chronic kidney disease","volume":"21","author":"Miguel","year":"2025","journal-title":"Nat. Rev. Nephrol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.cmet.2021.04.004","article-title":"KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease","volume":"33","author":"Mori","year":"2021","journal-title":"Cell. Metab."},{"key":"B39","doi-asserted-by":"publisher","first-page":"C999","DOI":"10.1152\/ajpcell.00201.2023","article-title":"Hypoxia and renal fibrosis","volume":"325","author":"Naas","year":"2023","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/j.freeradbiomed.2025.02.020","article-title":"TIMP2-mediated mitochondrial fragmentation and glycolytic reprogramming drive renal fibrogenesis following ischemia-reperfusion injury","volume":"232","author":"Pang","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1186\/s10020-025-01320-4","article-title":"Pyruvate kinase M2 activation maintains mitochondrial metabolism by regulating the interaction between HIF-1alpha and PGC-1alpha in diabetic kidney disease","volume":"31","author":"Park","year":"2025","journal-title":"Mol. Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"178560","DOI":"10.1016\/j.ejphar.2026.178560","article-title":"Safety of metformin in chronic kidney disease and type 2 diabetes mellitus: a systematic review and meta-analysis","volume":"1015","author":"Pati\u00f1o-Cardona","year":"2026","journal-title":"Eur. J. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1147414","DOI":"10.3389\/fphar.2023.1147414","article-title":"Research progress of glutathione peroxidase family (GPX) in redoxidation","volume":"14","author":"Pei","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1080\/21691401.2017.1396996","article-title":"Fabrication of niclosamide loaded solid lipid nanoparticles: in vitro characterization and comparative in vivo evaluation","volume":"46","author":"Rehman","year":"2018","journal-title":"Artif. Cells Nanomed Biotechnol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"17088","DOI":"10.1038\/nrdp.2017.88","article-title":"Chronic kidney disease","volume":"3","author":"Romagnani","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B46","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/s0955-0674(00)00194-0","article-title":"HIF-1 and mechanisms of hypoxia sensing","volume":"13","author":"Semenza","year":"2001","journal-title":"Curr. Opin. Cell. Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.redox.2015.01.002","article-title":"Oxidative stress: a concept in redox biology and medicine","volume":"4","author":"Sies","year":"2015","journal-title":"Redox Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/978-981-13-8871-2_29","article-title":"Oxidative stress and renal fibrosis: mechanisms and therapies","volume":"1165","author":"Su","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1161\/CIRCRESAHA.123.322494","article-title":"LTBP4 protects against renal fibrosis via mitochondrial and vascular impacts","volume":"133","author":"Su","year":"2023","journal-title":"Circ. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"103942","DOI":"10.1016\/j.ebiom.2022.103942","article-title":"Hypoxia and chronic kidney disease","volume":"77","author":"Wang","year":"2022","journal-title":"EBioMedicine"},{"key":"B51","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.kint.2024.04.016","article-title":"The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-kappaB family activation","volume":"106","author":"Wang","year":"2024","journal-title":"Kidney Int."},{"key":"B52","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.cmet.2023.11.017","article-title":"Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism","volume":"36","author":"Wedan","year":"2024","journal-title":"Cell. Metab."},{"key":"B53","doi-asserted-by":"publisher","first-page":"121033","DOI":"10.1016\/j.lfs.2022.121033","article-title":"Advances in energy metabolism in renal fibrosis","volume":"312","author":"Wei","year":"2023","journal-title":"Life Sci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2587326","DOI":"10.1080\/07853890.2025.2587326","article-title":"The lactate-lactylation axis in renal fibrosis: potential mechanisms in diabetic kidney disease","volume":"57","author":"Wei","year":"2025","journal-title":"Ann. Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"156324","DOI":"10.1016\/j.phymed.2024.156324","article-title":"Inhibition of PKM2 by shikonin impedes TGF-beta1 expression by repressing histone lactylation to alleviate renal fibrosis","volume":"136","author":"Xiang","year":"2025","journal-title":"Phytomedicine"},{"key":"B56","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1038\/s41419-022-05305-7","article-title":"Bone marrow mesenchymal stem cell-derived exosomal miR-21a-5p alleviates renal fibrosis by attenuating glycolysis by targeting PFKM","volume":"13","author":"Xu","year":"2022","journal-title":"Cell. Death Dis."},{"key":"B57","doi-asserted-by":"publisher","first-page":"115105","DOI":"10.1016\/j.intimp.2025.115105","article-title":"Succinate links TCA cycle dysfunction to inflammation by activating HIF-1alpha signaling in acute kidney injury","volume":"161","author":"Xu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/nrneph.2017.126","article-title":"CD36 in chronic kidney disease: novel insights and therapeutic opportunities","volume":"13","author":"Yang","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/s41419-023-06347-1","article-title":"Inhibition of PFKP in renal tubular epithelial cell restrains TGF-beta induced glycolysis and renal fibrosis","volume":"14","author":"Yang","year":"2023","journal-title":"Cell. Death Dis."},{"key":"B61","doi-asserted-by":"publisher","first-page":"3757","DOI":"10.1016\/j.ymthe.2025.05.013","article-title":"Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis","volume":"33","author":"Yu","year":"2025","journal-title":"Mol. Ther."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1038\/s41418-024-01365-8","article-title":"Deficiency of thiosulfate sulfurtransferase mediates the dysfunction of renal tubular mitochondrial fatty acid oxidation in diabetic kidney disease","volume":"31","author":"Zhang","year":"","journal-title":"Cell. Death Differ."},{"key":"B63","doi-asserted-by":"publisher","first-page":"103246","DOI":"10.1016\/j.redox.2024.103246","article-title":"Lactate drives epithelial-mesenchymal transition in diabetic kidney disease via the H3K14la\/KLF5 pathway","volume":"75","author":"Zhang","year":"","journal-title":"Redox Biol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"189107","DOI":"10.1016\/j.bbcan.2024.189107","article-title":"Decoding mitochondria's role in immunity and cancer therapy","volume":"1879","author":"Zhang","year":"","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"B65","doi-asserted-by":"publisher","first-page":"156738","DOI":"10.1016\/j.phymed.2025.156738","article-title":"Diosmin attenuates UUO-induced renal ferroptosis and fibrosis by inhibiting the HIF-1\u03b1\/FABP4 signaling axis","volume":"141","author":"Zhao","year":"2025","journal-title":"Phytomedicine"},{"key":"B66","doi-asserted-by":"publisher","first-page":"155978","DOI":"10.1016\/j.metabol.2024.155978","article-title":"Cannabinoid receptor 2 plays a key role in renal fibrosis through inhibiting lipid metabolism in renal tubular cells","volume":"159","author":"Zhou","year":"2024","journal-title":"Metabolism"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1849072\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:34:54Z","timestamp":1782970494000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1849072\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":62,"alternative-id":["10.3389\/fcell.2026.1849072"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1849072","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]},"article-number":"1849072"}}