{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:01:20Z","timestamp":1790834480655,"version":"4.1.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cisplatin-induced acute kidney injury (Cis-AKI) is a multifactorial nephrotoxic syndrome involving proximal tubular injury, oxidative and inflammatory stress, mitochondrial dysfunction, metabolic disturbance, and regulated cell death. However, the molecular targets linking cisplatin-associated toxicogenomic changes to AKI remain incompletely characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated network toxicology, transcriptomic analysis, single-nucleus RNA sequencing, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments to investigate candidate molecular targets in Cis-AKI. Cisplatin-associated toxicogenomic genes were intersected with AKI-related genes, and the shared candidates were analyzed using functional enrichment, protein\u2013protein interaction networks, CytoHubba, and MCODE. Prioritized genes were further examined in a cisplatin-induced mouse Acute kidney injury transcriptomic dataset, a human AKI kidney single-nucleus dataset, proximal tubular pseudotime analysis, and cisplatin-treated BUMPT proximal tubular cells. NicheNet analysis, knockout phenotype annotation, miRNA prediction, candidate compound screening, and molecular docking were also performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 214 shared genes were identified between the cisplatin-associated and AKI-related gene sets. These genes were mainly enriched in cellular respiration, electron transport, oxidoreductase activity, respiratory-chain complexes, and oxidative phosphorylation. Network analysis prioritized SDHB and NDUFAB1 within the respiration-associated gene network. In the cisplatin-induced mouse AKI dataset, Aco2, Aco1, Sdhb, and Aldh2 were significantly upregulated under stringent criteria, whereas additional respiration- and metabolism-related genes, including Ndufab1, met a secondary differential expression threshold. Human single-nucleus analysis revealed distinct cell-type-specific expression patterns of SDHB and NDUFAB1, with increased SDHB and decreased NDUFAB1 expression in proximal tubular cells. Pseudotime analysis showed a more pronounced late-stage increase in SDHB, whereas NDUFAB1 displayed weaker dynamics. In cisplatin-treated BUMPT cells, Havcr1 and Lcn2 were increased, Bcl2 was decreased, and Casp3 was increased. Among the selected candidate genes, Sdhb, Aco2, Aldh2, Ndufs2, and Uqcrc1 were upregulated, whereas Ndufab1 showed a modest decrease. NicheNet analysis further suggested that TGFB1-related signaling may contribute to proximal tubular transcriptional remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study prioritizes SDHB and NDUFAB1 within a respiration-associated gene network in Cis-AKI and demonstrates that they exhibit distinct expression patterns during proximal tubular injury. These findings highlight respiration-associated remodeling and proximal tubular state transition in cisplatin-induced kidney injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1939354","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:40:55Z","timestamp":1790833255000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated toxicogenomic and single-nucleus transcriptomic analyses prioritize SDHB and NDUFAB1 in mitochondrial respiration-associated remodeling during cisplatin-induced acute kidney injury"],"prefix":"10.3389","volume":"14","author":[{"given":"Dianjie","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital at Central South University","place":["Changsha, Hunan, China"]},{"name":"Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhui","family":"He","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Third Xiangya Hospital at Central South University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijie","family":"Hu","sequence":"additional","affiliation":[{"name":"Guangdong Medical University","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuzheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital at Central South University","place":["Changsha, Hunan, China"]},{"name":"Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changkun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital at Central South University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.3390\/antiox13121534","article-title":"JP4-039 mitigates cisplatin-induced acute kidney injury by inhibiting oxidative stress and blocking apoptosis and ferroptosis in mice","volume":"13","author":"Airik","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"NicheNet: modeling intercellular communication by linking ligands to target genes","volume":"17","author":"Browaeys","year":"2020","journal-title":"Nat. Methods"},{"key":"B3","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"Butler","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1038\/s41419-023-05830-z","article-title":"Single-cell sequencing reveals homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced AKI","volume":"14","author":"Chen","year":"2023","journal-title":"Cell Death and Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1016\/S0002-9440(10)61234-5","article-title":"Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2","volume":"167","author":"Ciarimboli","year":"2005","journal-title":"Am. J. Pathol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1111\/febs.70302","article-title":"Single-cell RNA sequencing reveals the protective role of renal Cx3cr1(+) macrophages in cisplatin-induced acute kidney injury","volume":"293","author":"Deng","year":"2026","journal-title":"Febs J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1074\/mcp.RA119.001784","article-title":"The mitochondrial acyl-carrier protein interaction network highlights important roles for LYRM family members in complex I and mitoribosome assembly","volume":"19","author":"Dibley","year":"2020","journal-title":"Mol. Cell Proteomics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock vina 1.2.0: new docking methods, expanded force field, and python bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model"},{"key":"B9","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/clpt.2009.139","article-title":"Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity","volume":"86","author":"Filipski","year":"2009","journal-title":"Clin. Pharmacol. Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e2026684118","DOI":"10.1073\/pnas.2026684118","article-title":"Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury","volume":"118","author":"Gerhardt","year":"2021","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.3390\/antiox12071477","article-title":"Complex II biology in aging, health, and disease","volume":"12","author":"Goetzman","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"10596","DOI":"10.1096\/fj.201900943R","article-title":"TGF-\u03b21-p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications","volume":"33","author":"Higgins","year":"2019","journal-title":"Faseb J."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3011","DOI":"10.3390\/ijms20123011","article-title":"Recent advances in models, mechanisms, biomarkers, and interventions in cisplatin-induced acute kidney injury","volume":"20","author":"Holditch","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/s41422-019-0208-x","article-title":"NDUFAB1 confers cardio-protection by enhancing mitochondrial bioenergetics through coordination of respiratory complex and supercomplex assembly","volume":"29","author":"Hou","year":"2019","journal-title":"Cell Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/s41581-022-00539-2","article-title":"Experimental models of acute kidney injury for translational research","volume":"18","author":"Hukriede","year":"2022","journal-title":"Nat. Rev. Nephrol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2980","DOI":"10.7150\/ijbs.96812","article-title":"CD8 T cells induce the peritubular capillary rarefaction during AKI to CKD transition","volume":"20","author":"Jiang","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/s41572-021-00284-z","article-title":"Acute kidney injury","volume":"7","author":"Kellum","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"B19","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1053\/j.ajkd.2023.01.446","article-title":"Metformin use and long-term clinical outcomes in kidney transplant recipients","volume":"82","author":"Kwon","year":"2023","journal-title":"Am. J. Kidney Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"109271","DOI":"10.1016\/j.isci.2024.109271","article-title":"A transfer learning framework to elucidate the clinical relevance of altered proximal tubule cell states in kidney disease","volume":"27","author":"Legouis","year":"2024","journal-title":"iScience"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1365802","DOI":"10.3389\/fphar.2024.1365802","article-title":"Arachidonic acid metabolism as a therapeutic target in AKI-to-CKD transition","volume":"15","author":"Li","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"504","DOI":"10.3390\/toxics14060504","article-title":"Molecular mechanisms of 6PPD and 6PPD-Q toxicity in neurodegenerative diseases: a network toxicology and experimental validation study","volume":"14","author":"Li","year":"","journal-title":"Toxics"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s11030-026-11528-z","article-title":"Unraveling the molecular landscape and therapeutic strategies for acute kidney injury: insights from transcriptomics, network pharmacology, virtual screening, and in vitro experiments","author":"Li","year":"","journal-title":"Mol. Divers"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/imna-d-23-00016","article-title":"Association of serum bicarbonate level with mortality in patients with acute kidney injury: a retrospective cohort study","volume":"11","author":"Ling","year":"2024","journal-title":"Integr. Med. Nephrol. Androl."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2879","DOI":"10.1097\/JS9.0000000000003742","article-title":"Integrated multi-omics and causal inference framework with experimental validation reveals key drivers of air pollution\u2013induced acute kidney injury","volume":"112","author":"Liu","year":"","journal-title":"Int. J. Surg"},{"key":"B26","doi-asserted-by":"publisher","first-page":"146096","DOI":"10.1016\/j.ijbiomac.2025.146096","article-title":"Molecular characterization and functional prioritization of CD46, IL6R, KLRC1, LEAP2 and SMOX as candidate targets in acute kidney injury","volume":"320","author":"Liu","year":"","journal-title":"Int. J. Biol. Macromol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.cmet.2025.10.006","article-title":"Therapeutic remodeling of the ceramide backbone prevents kidney injury","volume":"38","author":"Nicholson","year":"2026","journal-title":"Cell Metab."},{"key":"B28","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.kint.2020.04.020","article-title":"Controversies in acute kidney injury: conclusions from a kidney disease: improving global outcomes (KDIGO) conference","volume":"98","author":"Ostermann","year":"2020","journal-title":"Kidney Int."},{"key":"B29","doi-asserted-by":"publisher","first-page":"00064","DOI":"10.1097\/imna-d-25-00064","article-title":"Traditional Chinese medicine ameliorates acute kidney injury and chronic kidney disease by enhancing Keap1\/Nrf2 pathway","volume":"13","author":"Pang","year":"2026","journal-title":"Integr. Med. Nephrol. Androl."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.3389\/fmed.2022.873739","article-title":"Isoliquiritin ameliorates cisplatin-induced renal proximal tubular cell injury by antagonizing apoptosis, oxidative stress and inflammation","volume":"9","author":"Pei","year":"2022","journal-title":"Front. Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"93322","DOI":"10.5527\/wjn.v13.i2.93322","article-title":"Obstructive uropathy: overview of the pathogenesis, etiology and management of a prevalent cause of acute kidney injury","volume":"13","author":"P\u00e9rez-Aizpurua","year":"2024","journal-title":"World J. Nephrol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-Sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B33","first-page":"1949","volume-title":"Acute kidney injury. Lancet","author":"Ronco","year":"2019"},{"key":"B34","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.kint.2018.08.036","article-title":"Long-term risk of adverse outcomes after acute kidney injury: a systematic review and meta-analysis of cohort studies using consensus definitions of exposure","volume":"95","author":"See","year":"2019","journal-title":"Kidney Int."},{"key":"B35","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1007\/s10822-010-9352-6","article-title":"Ligand docking and binding site analysis with PyMOL and autodock\/vina","volume":"24","author":"Seeliger","year":"2010","journal-title":"J. Comput. Aided Mol. Des."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.7150\/ijbs.104107","article-title":"Tetramethylpyrazine attenuates sodium arsenite-induced acute kidney injury by improving the autophagic flux blockade via a YAP1-Nrf2-p62-dependent mechanism","volume":"21","author":"Song","year":"2025","journal-title":"Int. J. Biol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/s11658-026-00974-0","article-title":"PRKN mediates the ubiquitination of SCAF8 to reduce the mRNA stability of KLF5 and its transcriptional activation of EFNA3 in colorectal cancer","volume":"31","author":"Song","year":"","journal-title":"Cell Mol. Biol. Lett."},{"key":"B39","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/s13062-026-00778-4","article-title":"Multi-omics analysis of deep brain stimulation associated with brain-gut axis modulation and symptom amelioration in a Parkinson\u2019s disease mouse model","volume":"21","author":"Song","year":"","journal-title":"Biol. Direct"},{"key":"B40","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1186\/s12864-018-4772-0","article-title":"Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics","volume":"19","author":"Street","year":"2018","journal-title":"BMC Genomics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1038\/s41419-024-07231-2","article-title":"Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis","volume":"15","author":"Su","year":"2024","journal-title":"Cell Death and Dis."},{"key":"B42","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/tpj.2017.17","article-title":"Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity","volume":"18","author":"Sutherland","year":"2018","journal-title":"Pharmacogenomics J."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1511216","DOI":"10.1155\/2024\/1511216","article-title":"The renin-angiotensin system involvement in cisplatin-induced nephrotoxicity: an overview of physiological and pathological Mechanisms-A systematic review","volume":"2024","author":"Vakilian","year":"2024","journal-title":"Int. J. Nephrol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1007\/s00134-022-06851-6","article-title":"Delivering optimal renal replacement therapy to critically ill patients with acute kidney injury","volume":"48","author":"Wald","year":"2022","journal-title":"Intensive Care Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1097\/imna-d-25-00037","article-title":"Traditional Chinese medicine phytochemicals: promising therapeutic agents for acute kidney injury","volume":"12","author":"Wang","year":"2025","journal-title":"Integr. Med. Nephrol. Androl."},{"key":"B46","doi-asserted-by":"publisher","first-page":"4551","DOI":"10.7150\/ijbs.98627","article-title":"Mitochondrial pyruvate carrier 2 mitigates acute kidney injury via sustaining mitochondrial metabolism","volume":"20","author":"Wu","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41581-023-00758-1","article-title":"Designing acute kidney injury clinical trials","volume":"20","author":"Zarbock","year":"2024","journal-title":"Nat. Rev. Nephrol."},{"key":"B48","doi-asserted-by":"crossref","DOI":"10.1016\/j.omtn.2026.102964","article-title":"Cell type-stratified immunogenetic framework reveals immune drivers and therapeutic targets in kidney stone disease","volume-title":"Molecular Therapy Nucleic Acids","author":"Zeng","year":""},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1007\/s11030-026-11671-7","article-title":"Multi-omics and genetic prioritization identify candidate molecular links between micro- and nanoplastics-associated signatures and chronic kidney disease","author":"Zeng","year":"","journal-title":"Mol. Divers"},{"key":"B50","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1016\/j.cmet.2023.03.014","article-title":"Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight","volume":"35","author":"Zhang","year":"2023","journal-title":"Cell Metab."},{"key":"B51","doi-asserted-by":"publisher","first-page":"647","DOI":"10.3390\/toxics14080647","article-title":"Long-term oral exposure to chlorophenylacetonitrile induces gastrointestinal morphological alterations and splenic transcriptomic reprogramming in mice","volume":"14","author":"Zhang","year":"2026","journal-title":"Toxics"},{"key":"B52","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/s13020-024-01024-7","article-title":"Protective effect of huashi baidu formula against AKI and active ingredients that target SphK1 and PAI-1","volume":"19","author":"Zhong","year":"2024","journal-title":"Chin. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"5223","DOI":"10.7150\/ijbs.115364","article-title":"Targeting NINJ1-Mediated plasma membrane rupture in tubular epithelial cell prevents inflammatory response in acute kidney injury","volume":"21","author":"Zhou","year":"2025","journal-title":"Int. J. Biol. Sci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e70135","DOI":"10.1002\/imt2.70135","article-title":"A spatiotemporal single-cell atlas of porcine development reveals regulatory dynamics and cellular targets of domestication","volume":"5","author":"Zhou","year":"2026","journal-title":"Imeta"},{"key":"B55","doi-asserted-by":"publisher","first-page":"e2408839","DOI":"10.1002\/advs.202408839","article-title":"Genome-wide silencer screening reveals key silencer modulating reprogramming efficiency in mouse induced pluripotent stem cells","volume":"12","author":"Zhu","year":"2025","journal-title":"Adv. Sci. (Weinh)"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1939354\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:40:56Z","timestamp":1790833256000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1939354\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":55,"alternative-id":["10.3389\/fcell.2026.1939354"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1939354","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"1939354"}}