{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:07:35Z","timestamp":1789135655610,"version":"build-2803163510"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["58\/16\/2020\/PHA\/BMS"],"award-info":[{"award-number":["58\/16\/2020\/PHA\/BMS"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Calcium oxalate monohydrate (COM) crystals are major contributors to nephrolithiasis-associated renal tubular injury, primarily through mechanisms involving oxidative stress, inflammation, apoptosis, and epithelial\u2013mesenchymal transition (EMT). While nesfatin-1 is known for its antioxidant and cytoprotective actions, the specific role of endogenous nesfatin-1 in regulating COM-induced epithelial injury has not been fully defined. In this study, nesfatin-1 was silenced using antisense oligonucleotides in NRK-52E and primary renal tubular epithelial cells to examine how loss of endogenous nesfatin-1 peptide influences cellular susceptibility to COM. COM exposure reduced nesfatin-1 levels, and this decline was markedly greater in the nesfatin-1 silenced + COM group. Silencing nesfatin-1 intensified COM-driven oxidative stress, as reflected by reduced catalase activity and increased levels of malondialdehyde, nitric oxide, and ROS. Pro-inflammatory markers including NF-\u03baB, TNF-\u03b1, IL-6, and IL-1\u03b2 were upregulated, whereas IL-10 was decreased. Apoptotic indicators such as elevated intracellular Ca2+, diminished Bcl-2, increased caspase-3 activation, and higher proportions of apoptotic and necrotic cells were also evident. EMT and fibrotic markers (TGF-\u03b21, \u03b1-SMA, Smad2\/3, Smad4, vimentin) were increased, alongside reduced E-cadherin expression. Exogenous nesfatin-1 mitigated oxidative, inflammatory, apoptotic, and fibrotic responses in COM-treated cells; however, these protective effects were minimal in nesfatin-1 silenced + COM cells. Overall, the findings demonstrate that endogenous nesfatin-1 is indispensable for maintaining epithelial stability under COM-induced stress, and its absence amplifies cellular injury while diminishes responsiveness to exogenous peptide. Nesfatin-1 thus emerges as a potential therapeutic target for limiting crystal-induced renal cells damage.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00200","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T07:01:44Z","timestamp":1786950104000},"page":"2544-2559","source":"Crossref","is-referenced-by-count":0,"title":["Nesfatin-1\nDeficiency Exacerbates Calcium Oxalate\nMonohydrate\u2013Induced Cellular Injury in Renal Epithelial Cells"],"prefix":"10.1021","volume":"9","author":[{"given":"Ganesh Panditrao","family":"Lahane","sequence":"first","affiliation":[{"name":"Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus , , Jawahar Nagar, Shameerpet , , ,","place":["Hyderabad, Telangana, India, 500078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1892-6875","authenticated-orcid":true,"given":"Arti","family":"Dhar","sequence":"additional","affiliation":[{"name":"Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus , , Jawahar Nagar, Shameerpet , , ,","place":["Hyderabad, Telangana, India, 500078"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"2026091109134795900_cit1","doi-asserted-by":"publisher","first-page":"5733","DOI":"10.1097\/JS9.0000000000001719","article-title":"Risk factors\nfor nephrolithiasis\nformation: An umbrella review","volume":"110","author":"Ma","year":"2024","journal-title":"Int. J. Surg."},{"key":"2026091109134795900_cit2","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.2147\/IJGM.S459155","article-title":"Current dietary and\nmedical prevention of renal calcium oxalate stones","volume":"17","author":"Wang","year":"2024","journal-title":"Int. J. Gen. Med."},{"key":"2026091109134795900_cit3","first-page":"118","article-title":"Calcium oxalate crystals:\nEpidemiology, causes, modeling of crystal formation and treatment\nmanagement","volume":"13","author":"Susilo","year":"2021","journal-title":"J. Pharm. Sci. Res."},{"key":"2026091109134795900_cit4","doi-asserted-by":"publisher","first-page":"15055","DOI":"10.1038\/cddiscovery.2015.55","article-title":"Calcium\noxalate toxicity in renal\nepithelial cells: The mediation of crystal size on cell death mode","volume":"1","author":"Sun","year":"2015","journal-title":"Cell Death Discovery"},{"key":"2026091109134795900_cit5","doi-asserted-by":"publisher","first-page":"6039","DOI":"10.1021\/acsomega.7b00510","article-title":"Effect\nof crystal shape and aggregation of calcium\noxalate monohydrate on cellular toxicity in renal epithelial cells","volume":"2","author":"Sun","year":"2017","journal-title":"ACS Omega"},{"key":"2026091109134795900_cit6","doi-asserted-by":"publisher","first-page":"664563","DOI":"10.1101\/2025.07.13.664563","article-title":"In vitro knockdown\nand pharmacological\ninhibition of RIPK2 attenuates calcium oxalate\u2013nephrocalcinosis-associated\ninflammation and oxidative stress in NRK-52E and primary renal epithelial\ncells","author":"Lahane","year":"2025","journal-title":"bioRxiv"},{"key":"2026091109134795900_cit7","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s10157-004-0292-0","article-title":"Crystal-induced\ninflammation of the kidneys: Results from human studies, animal models,\nand tissue-culture studies","volume":"8","author":"Khan","year":"2004","journal-title":"Clin. Exp. Nephrol."},{"key":"2026091109134795900_cit8","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s00240-025-01808-y","article-title":"Oxidative\nstress, inflammation and kidney stones","volume":"53","author":"Khan","year":"2025","journal-title":"Urolithiasis"},{"key":"2026091109134795900_cit9","doi-asserted-by":"publisher","first-page":"256","DOI":"10.3978\/j.issn.2223-4683.2014.06.04","article-title":"Reactive\noxygen species, inflammation and calcium oxalate nephrolithiasis","volume":"3","author":"Khan","year":"2014","journal-title":"Transl. Androl. Urol."},{"key":"2026091109134795900_cit10","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s00240-025-01826-w","article-title":"Apoptosis, ferroptosis,\nnecrosis, necroptosis and pyroptosis\nin the formation of calcium oxalate kidney stones","volume":"53","author":"Khan","year":"2025","journal-title":"Urolithiasis"},{"key":"2026091109134795900_cit11","doi-asserted-by":"publisher","first-page":"116284","DOI":"10.1016\/j.bcp.2024.116284","article-title":"Renoprotective effect\nof nesfatin-1 in adenine-induced chronic kidney\ndisease: An in vitro and in vivo study","volume":"225","author":"Lahane","year":"2024","journal-title":"Biochem.\nPharmacol."},{"key":"2026091109134795900_cit12","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.23795","article-title":"Therapeutic\napproaches and novel\nantifibrotic agents in renal fibrosis: A comprehensive review","volume":"38","author":"Lahane","year":"2024","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"2026091109134795900_cit13","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00240-025-01794-1","article-title":"Reno-protection\nby Didymocarpus pedicellata against oxalate-induced damage: Mechanistic\ninsights into mitigation of oxidative stress-induced signaling pathways\nin renal cell line and rat model","volume":"53","author":"Singh","year":"2025","journal-title":"Urolithiasis"},{"key":"2026091109134795900_cit14","doi-asserted-by":"publisher","first-page":"5450","DOI":"10.1080\/21655979.2021.1955176","article-title":"Ursolic acid treats renal tubular epithelial cell damage\ninduced\nby calcium oxalate monohydrate via inhibiting oxidative stress and\ninflammation","volume":"12","author":"Jia","year":"2021","journal-title":"Bioengineered"},{"key":"2026091109134795900_cit15","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.70593","article-title":"Nucleobindin-2-derived\nmultifunctional\npeptide nesfatin-1: Renoprotective mechanisms and therapeutic promise","volume":"39","author":"Lahane","year":"2025","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"2026091109134795900_cit16","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1227\/NEU.0b013e318210f258","article-title":"The novel function of nesfatin-1 as an anti-inflammatory\nand antiapoptotic peptide in subarachnoid hemorrhage-induced oxidative\nbrain damage in rats","volume":"68","author":"O\u0308zsavc\u0131","year":"2011","journal-title":"Neurosurgery"},{"key":"2026091109134795900_cit17","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.peptides.2012.04.014","article-title":"The anti-inflammatory\nand anti-apoptotic effects of nesfatin-1 in the traumatic rat brain","volume":"36","author":"Tang","year":"2012","journal-title":"Peptides"},{"key":"2026091109134795900_cit18","doi-asserted-by":"publisher","first-page":"882","DOI":"10.3109\/0886022X.2015.1015426","article-title":"The protective effect of nesfatin-1\nagainst renal ischemia-reperfusion injury in rats","volume":"37","author":"Jiang","year":"2015","journal-title":"Ren. Fail."},{"key":"2026091109134795900_cit19","doi-asserted-by":"publisher","first-page":"607","DOI":"10.2147\/JIR.S273446","article-title":"Antioxidant, anti-inflammatory\nand anti-apoptotic activities of nesfatin-1:\nA review","volume":"13","author":"Xu","year":"2020","journal-title":"J. Inflamm. Res."},{"key":"2026091109134795900_cit20","doi-asserted-by":"publisher","first-page":"833","DOI":"10.3892\/etm.2021.10265","article-title":"Protective role and molecular mechanism of action of nesfatin-1 against\nhigh glucose-induced inflammation, oxidative stress and apoptosis\nin retinal epithelial cells","volume":"22","author":"Sun","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"2026091109134795900_cit21","doi-asserted-by":"publisher","first-page":"171013","DOI":"10.1016\/j.peptides.2023.171013","article-title":"Nesfatin-1 peptide protects rat renal epithelial cells against high\nglucose- and H2O2-induced injury via inhibition\nof oxidative stress, apoptosis, and fibrosis","volume":"165","author":"Lahane","year":"2023","journal-title":"Peptides"},{"key":"2026091109134795900_cit22","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1093\/ndt\/gfac053","article-title":"Nesfatin-1\ntreatment preserves antioxidant status and attenuates renal fibrosis\nin rats with unilateral ureteral obstruction","volume":"37","author":"Tezcan","year":"2022","journal-title":"Nephrol. Dial. Transplant."},{"key":"2026091109134795900_cit23","doi-asserted-by":"publisher","DOI":"10.3791\/57718","article-title":"Isolation, characterization, and\nhigh-throughput extracellular flux analysis of mouse primary renal\ntubular epithelial cells","volume":"136","author":"Ding","year":"2018","journal-title":"J. Vis. Exp."},{"key":"2026091109134795900_cit24","doi-asserted-by":"publisher","first-page":"178390","DOI":"10.1016\/j.ejphar.2025.178390","article-title":"Angiotensin II-induced\nfibrosis is mediated by activation of FGFR1 pathway in renal epithelial\ncells: Attenuation by chimeric peptide","volume":"1009","author":"Venkadakrishnan","year":"2025","journal-title":"Eur.\nJ. Pharmacol."},{"key":"2026091109134795900_cit25","doi-asserted-by":"publisher","first-page":"114652","DOI":"10.1016\/j.yexcr.2025.114652","article-title":"PKR inhibition reduces\nhigh glucose- and H2O2-induced injury in rat\nrenal epithelial cells by suppressing the sonic hedgehog pathway","volume":"450","author":"Lahane","year":"2025","journal-title":"Exp. Cell Res."},{"key":"2026091109134795900_cit26","doi-asserted-by":"publisher","first-page":"120762","DOI":"10.1016\/j.lfs.2022.120762","article-title":"Downregulation of nesfatin-1\nexpression in acute kidney injury in\nvivo in Wistar rats and in vitro in cultured cells","volume":"305","author":"Goyal","year":"2022","journal-title":"Life Sci."},{"key":"2026091109134795900_cit27","doi-asserted-by":"publisher","first-page":"5050","DOI":"10.1111\/jcmm.16481","article-title":"Nesfatin-1 inhibits\nmyocardial ischaemia\/reperfusion injury through activating Akt\/ERK\npathway-dependent attenuation of endoplasmic reticulum stress","volume":"25","author":"Su","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"2026091109134795900_cit28","doi-asserted-by":"publisher","first-page":"110369","DOI":"10.1016\/j.intimp.2023.110369","article-title":"Nesfatin-1,\na novel energy-regulating peptide, alleviates pulmonary fibrosis by\nblocking the TGF-\u03b21\/Smad pathway in an AMPK\u03b1-dependent\nmanner","volume":"120","author":"Zhang","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"2026091109134795900_cit29","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s13019-022-01952-1","article-title":"Nesfatin-1\nalleviated lipopolysaccharide-induced\nacute lung injury through regulating inflammatory response associated\nwith macrophage modulation","volume":"17","author":"Cheng","year":"2022","journal-title":"J. Cardiothorac.\nSurg."},{"key":"2026091109134795900_cit30","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1007\/s10989-022-10429-7","article-title":"Modulation of apoptosis\nand oxidative stress with nesfatin-1 in doxorubicin-induced\ncardiotoxicity in male rats","volume":"28","author":"Rakhshan","year":"2022","journal-title":"Int. J. Pept. Res.\nTher."},{"key":"2026091109134795900_cit31","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s11011-018-0323-2","article-title":"Protective effects\nof nesfatin-1 peptide on cerebral ischemia-reperfusion injury via\ninhibition of neuronal cell death and enhancement of antioxidant defenses","volume":"34","author":"Erfani","year":"2019","journal-title":"Metab. Brain Dis."},{"key":"2026091109134795900_cit32","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.jss.2014.06.057","article-title":"Nesfatin-1 alleviates gastric damage\nvia direct antioxidant mechanisms","volume":"193","author":"Kolgazi","year":"2015","journal-title":"J. Surg.\nRes."},{"key":"2026091109134795900_cit33","first-page":"741","article-title":"Anti-inflammatory\neffects of nesfatin-1 in rats with\nacetic acid-induced colitis and underlying mechanisms","volume":"66","author":"Ozturk","year":"2015","journal-title":"J. Physiol. Pharmacol."},{"key":"2026091109134795900_cit34","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1016\/S0891-5849(00)00221-5","article-title":"Protein kinase C signaling and oxidative stress","volume":"28","author":"Gopalakrishna","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"2026091109134795900_cit35","doi-asserted-by":"publisher","first-page":"F427","DOI":"10.1152\/ajprenal.90536.2008","article-title":"Advanced oxidation\nprotein products induce mesangial cell perturbation through PKC-dependent\nactivation of NADPH oxidase","volume":"296","author":"Wei","year":"2009","journal-title":"Am. J. Physiol.\nRenal Physiol."},{"key":"2026091109134795900_cit36","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.lfs.2016.08.026","article-title":"Kidney stone matrix\nproteins ameliorate calcium oxalate monohydrate-induced apoptotic\ninjury to renal epithelial cells","volume":"164","author":"Narula","year":"2016","journal-title":"Life Sci."},{"key":"2026091109134795900_cit37","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1096\/fasebj.9.2.7781924","article-title":"Calcium-mediated\ncell injury and cell death","volume":"9","author":"Trump","year":"1995","journal-title":"FASEB J."},{"key":"2026091109134795900_cit38","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1083\/jcb.200208089","article-title":"Caspase-mediated\nloss of mitochondrial\nfunction and generation of reactive oxygen species during apoptosis","volume":"160","author":"Ricci","year":"2003","journal-title":"J. Cell Biol."},{"key":"2026091109134795900_cit39","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/0014-5793(96)00989-1","article-title":"Why are\nmitochondria involved in apoptosis? Permeability transition pores\nand apoptosis as selective mechanisms to eliminate superoxide-producing\nmitochondria and cells","volume":"397","author":"Skulachev","year":"1996","journal-title":"FEBS Lett."},{"key":"2026091109134795900_cit40","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1007\/s12020-015-0648-0","article-title":"24 h nesfatin-1 treatment promotes apoptosis in cardiomyocytes","volume":"51","author":"Feijoo-Bandi\u0301n","year":"2016","journal-title":"Endocrine"},{"key":"2026091109134795900_cit41","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s40709-021-00147-4","article-title":"Nesfatin-1\nprotects H9c2 cardiomyocytes against cobalt\nchloride-induced hypoxic injury by modulating the MAPK and Notch1\nsignaling pathways","volume":"28","author":"Li","year":"2021","journal-title":"J. Biol. Res. (Thessalon.)"},{"key":"2026091109134795900_cit42","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/s41374-022-00774-y","article-title":"Nesfatin-1\nexerts protective effects on acidosis-stimulated chondrocytes and\nrats with adjuvant-induced arthritis by inhibiting ASIC1a expression","volume":"102","author":"Xu","year":"2022","journal-title":"Lab. Invest."},{"key":"2026091109134795900_cit43","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/s12031-018-1105-3","article-title":"Nesfatin-1 improves\nspatial memory impairment following transient global cerebral ischemia\/reperfusion\nvia inhibiting microglial and caspase-3 activation","volume":"65","author":"Erfani","year":"2018","journal-title":"J. Mol. Neurosci."}],"container-title":["ACS Pharmacology &amp; Translational\nScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsptsci.6c00200","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/9\/2544\/66608750\/acsptsci.6c00200.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/9\/2544\/66608750\/acsptsci.6c00200.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:20:53Z","timestamp":1789132853000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article\/9\/9\/2544\/5259564\/Nesfatin-1-Deficiency-Exacerbates-Calcium-Oxalate"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,17]]},"published-print":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsptsci.6c00200","relation":{},"ISSN":["2575-9108"],"issn-type":[{"value":"2575-9108","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]}}}