{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:01:42Z","timestamp":1786978902417,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82060801"],"award-info":[{"award-number":["82060801"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82060801"],"award-info":[{"award-number":["82060801"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Ginkgo biloba extract (GBe) attenuates the transition of cisplatin (CDDP)-induced acute kidney injury to chronic kidney disease (AKI-to-CKD). Purpose: This study aimed to reveal the mechanism by which GBe inhibits CDDP-induced AKI-to-CKD. The potential targets of GBe in alleviating CDDP-induced renal interstitial fibrosis (Cis-RIF) were predicted through network pharmacology. Transcriptomics and metabolomics were used to detect differentially expressed genes (DEGs) and metabolites (DEMs) in renal tissues from Cis-RIF rats. Integrated multi-omics analysis was performed to determine the potential mechanism underlying GBe inhibiting AKI-to-CKD, and experimental verification was conducted in vivo, in vitro, and using siRNA. We identified 100 targets of GBe that could inhibit Cis-RIF using network pharmacology, and these targets were enriched in 194 signaling pathways. Transcriptomics and metabolomics revealed 8907 DEGs (enriched in 51 pathways) and 424 DEMs (enriched in 16 pathways), respectively. Collectively, the phosphatidylinositol signaling pathway was a co-enriched pathway, which may be the key pathway through which GBe inhibits AKI-to-CKD. This was verified experimentally. The related apoptosis and fibrosis indicators, and the key targets of the phosphatidylinositol signaling pathway (PLC, PKC, PIP2, IP3, DAG, Ca2+), in rat renal tissues and renal tubular epithelial cells (RTECs) with CDDP-induced AKI-to-CKD were significantly increased. Inhibition of HIF-1\u03b1 and knockdown of HIF-1\u03b1 in RTECs reversed the changes the phosphatidylinositol pathway targets. Moreover, both GBe and the HIF-1\u03b1 inhibitor could inhibit HIF-1\u03b1 and the phosphatidylinositol pathway targets, as well as the apoptosis and EMT of RTECs. Conclusion: This study reveals for the first time that GBe may inhibit AKI-to-CKD by downregulating apoptosis and EMT in RTECs through the HIF-1\u03b1\/phosphatidylinositol signaling axis.<\/jats:p>","DOI":"10.3390\/cimb48080834","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:42:17Z","timestamp":1786974137000},"page":"834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ginkgo biloba Extract Inhibits Cisplatin-Induced Acute Kidney Injury-to-Chronic Kidney Disease Through Downregulating Apoptosis Mediated by the HIF-1\u03b1\/Phosphatidylinositol Pathway"],"prefix":"10.3390","volume":"48","author":[{"given":"Weimin","family":"Xu","sequence":"first","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Huang","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Chen","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Yang","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyuan","family":"Wan","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Ye","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songqing","family":"Huang","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20337","DOI":"10.1038\/s41598-020-77401-7","article-title":"Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer","volume":"10","author":"Lee","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41581-019-0248-y","article-title":"Targeting the progression of chronic kidney disease","volume":"16","author":"Lamas","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1093\/ckj\/sfaa127","article-title":"Preventive strategies for acute kidney injury in cancer patients","volume":"14","author":"Cosmai","year":"2021","journal-title":"Clin. Kidney J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"168121","DOI":"10.1016\/j.bbadis.2025.168121","article-title":"NR5A2 promotes epithelial-to-mesenchymal transition in renal fibrosis by targeting MMP25 transcription","volume":"1872","author":"Wang","year":"2026","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"F1501","DOI":"10.1152\/ajprenal.00195.2018","article-title":"Immune cells and inflammation in AKI to CKD progression","volume":"315","author":"Sato","year":"2018","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1093\/ckj\/sfaa164","article-title":"The complex interplay between kidney injury and inflammation","volume":"14","author":"McWilliam","year":"2021","journal-title":"Clin. Kidney J."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yao, M., Liu, L., Hao, Z., Shen, J., and Dai, C. (2026). A Narrative Review of Ginkgo biloba Extract: Biological Function, Molecular Mechanisms, and Applications in Animal Production. Antioxidants, 15.","DOI":"10.3390\/antiox15020251"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sun, L., Apweiler, M., Tirkey, A., Klett, D., Normann, C., Dietz, G.P.H., Lehner, M.D., and Fiebich, B.L. (2024). Anti-Neuroinflammatory Effects of Ginkgo biloba Extract EGb 761 in LPS-Activated BV2 Microglial Cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158108"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ovey, I.S., Ozsimsek, A., Velioglu, H.A., Altay, O., Mardinoglu, A., and Yulug, B. (2023). EGb 761 reduces Ca2+ influx and apoptosis after pentylenetetrazole treatment in a neuroblastoma cell line. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1195303"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9226","DOI":"10.1039\/D2FO01827F","article-title":"A critical review of ginkgolic acids in Ginkgo biloba leaf extract (EGb): Toxicity and technologies to remove ginkgolic acids and their promising bioactivities","volume":"13","author":"Boateng","year":"2022","journal-title":"Food Funct."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"154809","DOI":"10.1016\/j.phymed.2023.154809","article-title":"Ginkgo biloba extract attenuates cisplatin-induced renal interstitial fibrosis by inhibiting the activation of renal fibroblasts through down-regulating the HIF-1\u03b1\/STAT3\/IL-6 pathway in renal tubular epithelial cells","volume":"115","author":"Zhang","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13020-022-00574-y","article-title":"Ginkgo biloba leaf extract mitigates cisplatin-induced chronic renal interstitial fibrosis by inhibiting the epithelial-mesenchymal transition of renal tubular epithelial cells mediated by the Smad3\/TGF-\u03b21 and Smad3\/p38 MAPK pathways","volume":"17","author":"Wei","year":"2022","journal-title":"Chin. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.2147\/DDDT.S375281","article-title":"Integrated Metabonomics and Network Pharmacology to Reveal the Action Mechanism Effect of Shaoyao Decoction on Ulcerative Colitis","volume":"16","author":"Wu","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105486","DOI":"10.1016\/j.archger.2024.105486","article-title":"Integrating transcriptomic and proteomic data for a comprehensive molecular perspective on the association between sarcopenia and osteoporosis","volume":"125","author":"Chen","year":"2024","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pinu, F.R., Beale, D.J., Paten, A.M., Kouremenos, K., Swarup, S., Schirra, H.J., and Wishart, D. (2019). Systems Biology and Multi-Omics Integration: Viewpoints from the Metabolomics Research Community. Metabolites, 9.","DOI":"10.3390\/metabo9040076"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Di Minno, A., Gelzo, M., Caterino, M., Costanzo, M., Ruoppolo, M., and Castaldo, G. (2022). Challenges in Metabolomics-Based Tests, Biomarkers Revealed by Metabolomic Analysis, and the Promise of the Application of Metabolomics in Precision Medicine. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095213"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"118492","DOI":"10.1016\/j.jep.2024.118492","article-title":"Simiao pills alleviates renal injury associated with hyperuricemia: A multi-omics analysis","volume":"333","author":"Zeng","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"118977","DOI":"10.1016\/j.jep.2024.118977","article-title":"Integrating metabolomics with network pharmacology to reveal the mechanism of Poria cocos in hyperuricemia treatment","volume":"337","author":"Wang","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"156200","DOI":"10.1016\/j.phymed.2024.156200","article-title":"Multi-omics analysis reveals the protective effects of Chinese yam polysaccharide against cisplatin-induced renal interstitial fibrosis","volume":"136","author":"Wei","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1124\/molpharm.121.000354","article-title":"Senolytic-Mediated Elimination of Head and Neck Tumor Cells Induced Into Senescence by Cisplatin","volume":"101","author":"Ahmadinejad","year":"2022","journal-title":"Mol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, J., Liu, Q., Zhao, Y., Fu, J., and Su, J. (2023). Tumor Cells Transmit Drug Resistance via Cisplatin-Induced Extracellular Vesicles. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241512347"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"119120","DOI":"10.1016\/j.lfs.2021.119120","article-title":"Enoxaparin prevents CXCL16\/ADAM10-mediated cisplatin renal toxicity: Role of the coagulation system and the transcriptional factor NF-\u03baB","volume":"270","author":"Aboyoussef","year":"2021","journal-title":"Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kumakura, S., Sato, E., Sekimoto, A., Hashizume, Y., Yamakage, S., Miyazaki, M., Ito, S., Harigae, H., and Takahashi, N. (2021). Nicotinamide Attenuates the Progression of Renal Failure in a Mouse Model of Adenine-Induced Chronic Kidney Disease. Toxins, 13.","DOI":"10.3390\/toxins13010050"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.2967\/jnumed.119.232017","article-title":"Management of Patients with Renal Failure Undergoing Dialysis During (131)I Therapy for Thyroid Cancer","volume":"61","author":"Vermandel","year":"2020","journal-title":"J. Nucl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155592","DOI":"10.1016\/j.metabol.2023.155592","article-title":"Regulation of pericyte metabolic reprogramming restricts the AKI to CKD transition","volume":"145","author":"Xu","year":"2023","journal-title":"Metabolism"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1038\/s41419-022-05394-4","article-title":"IL-18 deficiency ameliorates the progression from AKI to CKD","volume":"13","author":"Luan","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S285","DOI":"10.3233\/JAD-231372","article-title":"Pharmacodynamic and Clinical Effects of Ginkgo biloba Extract EGb 761 and Its Phytochemical Components in Alzheimer\u2019s Disease","volume":"101","author":"Tartari","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"578101","DOI":"10.1016\/j.jneuroim.2023.578101","article-title":"Ginkgo biloba extract (EGb-761) confers neuroprotection against ischemic stroke by augmenting autophagic\/lysosomal signaling pathway","volume":"382","author":"Zang","year":"2023","journal-title":"J. Neuroimmunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"812","DOI":"10.14336\/AD.2017.0615","article-title":"Advances in the Studies of Ginkgo biloba Leaves Extract on Aging-Related Diseases","volume":"8","author":"Zuo","year":"2017","journal-title":"Aging Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"115645","DOI":"10.1016\/j.jep.2022.115645","article-title":"Leaves, seeds and exocarp of Ginkgo biloba L. (Ginkgoaceae): A Comprehensive Review of Traditional Uses, phytochemistry, pharmacology, resource utilization and toxicity","volume":"298","author":"Liu","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6657206","DOI":"10.1155\/2021\/6657206","article-title":"Ginkgo biloba Extract EGB761 Ameliorates the Extracellular Matrix Accumulation and Mesenchymal Transformation of Renal Tubules in Diabetic Kidney Disease by Inhibiting Endoplasmic Reticulum Stress","volume":"2021","author":"Han","year":"2021","journal-title":"BioMed Res. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3892\/br.2021.1414","article-title":"Ginaton injection alleviates cisplatin-induced renal interstitial fibrosis in rats via inhibition of apoptosis through regulation of the p38MAPK\/TGF-\u03b21 and p38MAPK\/HIF-1\u03b1 pathways","volume":"14","author":"Liang","year":"2021","journal-title":"Biomed. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"115434","DOI":"10.1016\/j.biopha.2023.115434","article-title":"Ootheca mantidis mitigates renal fibrosis in mice by the suppression of apoptosis via increasing the gut microbe Akkermansia muciniphila and modulating glutamine metabolism","volume":"166","author":"Wang","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"117986","DOI":"10.1016\/j.jep.2024.117986","article-title":"Demethylzeylasteral protects against renal interstitial fibrosis by attenuating mitochondrial complex I-mediated oxidative stress","volume":"327","author":"Shen","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112177","DOI":"10.1016\/j.biopha.2021.112177","article-title":"Integration of transcriptomics and metabolomics confirmed hepatoprotective effects of steamed shoot extracts of ginseng (Panax ginseng C.A. Meyer) on toxicity caused by overdosed acetaminophen","volume":"143","author":"Yao","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"118834","DOI":"10.1016\/j.jep.2024.118834","article-title":"Integrated network pharmacology, transcriptomics and metabolomics to explore the material basis and mechanism of Danggui-Baishao herb pair for treating hepatic fibrosis","volume":"337","author":"Zhang","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kanemaru, K., and Nakamura, Y. (2023). Activation Mechanisms and Diverse Functions of Mammalian Phospholipase C. Biomolecules, 13.","DOI":"10.3390\/biom13060915"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7622","DOI":"10.1523\/JNEUROSCI.0586-18.2018","article-title":"A Closely Associated Phospholipase C Regulates Cation Channel Function Through Phosphoinositide Hydrolysis","volume":"38","author":"Sturgeon","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"jcs222463","DOI":"10.1242\/jcs.222463","article-title":"IP(3) receptors\u2014Lessons from analyses ex cellula","volume":"132","author":"Rossi","year":"2018","journal-title":"J. Cell Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Young, M., Booth, D.M., Smith, D., Tigano, M., Hajn\u00f3czky, G., and Joseph, S.K. (2024). Transcriptional regulation in the absence of inositol trisphosphate receptor calcium signaling. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1473210"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1042\/BCJ20250280","article-title":"Protein kinase C theta: Evolution, regulation, and function","volume":"483","author":"Hodapp","year":"2026","journal-title":"Biochem. J."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/834\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:16:13Z","timestamp":1786976173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/834"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":41,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cimb48080834"],"URL":"https:\/\/doi.org\/10.3390\/cimb48080834","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]}}}