{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T17:21:13Z","timestamp":1786296073930,"version":"build-2736575974"},"reference-count":27,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2021-I2M-1-031"],"award-info":[{"award-number":["2021-I2M-1-031"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2017-I2M-1-013"],"award-info":[{"award-number":["2017-I2M-1-013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Forchlorfenuron is a widely used plant cytokinin in Traditional Chinese Medicine and agricultural cultivation to boost resistance, postpone senescence, and increase productivity. However, the improper use of forchlorfenuron results in excessive residues and contamination, raising health and safety concerns. Our research investigated the toxicity of forchlorfenuron on hepatocytes in vitro. Results showed that forchlorfenuron inhibited HepaRG cell viability in a concentration and time-dependent manner. Forchlorfenuron-induced cellular apoptosis and the increased intracellular reactive oxygen species (ROS) indicated the participation of oxidative stress. Molecular docking and network pharmacology data suggested that the hepatotoxicity of forchlorfenuron might involve the MAPK signaling pathway. After 24 h of forchlorfenuron exposure, the P38-MAP kinase, upstream kinases MKK3, and the transcription factor ATF2 were maximally activated. Apoptosis induced by forchlorfenuron was significantly reduced by pretreatment with the P38 inhibitor SB203580. These findings implicated that HepaRG hepatocyte injuries were generated by forchlorfenuron through the induction of cellular apoptosis via the MKK3\/P38\/ATF2 pathway. Forchlorfenuron application should be closely managed to prevent potential liver damage.<\/jats:p>","DOI":"10.3390\/ijms27052173","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T09:31:32Z","timestamp":1772098292000},"page":"2173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Forchlorfenuron Exposure Induces Hepatocyte Apoptosis via MKK3\/P38\/ATF2 Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Yunqi","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Luo","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Che","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziru","family":"Dai","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6415","DOI":"10.1021\/acs.jafc.3c00380","article-title":"Discovery and Identification of the Key Contributor to the Bitter Taste in Oriental Melon after Forchlorfenuron Application","volume":"71","author":"Wang","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"143059","DOI":"10.1016\/j.foodchem.2025.143059","article-title":"Pre-harvest application of forchlorfenuron enhances fruit quality and bioactive substance accumulation in Chunhua loquat","volume":"473","author":"Zhang","year":"2025","journal-title":"Food Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"112412","DOI":"10.1016\/j.foodres.2022.112412","article-title":"Key metabolites and mechanistic insights in forchlorfenuron controlling kiwifruit development","volume":"164","author":"Bi","year":"2022","journal-title":"Food Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.chembiol.2024.04.012","article-title":"The septin modifier, forchlorfenuron, activates NLRP3 via a potassium-independent mitochondrial axis","volume":"31","author":"Holley","year":"2024","journal-title":"Cell Chem. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.freeradbiomed.2025.12.021","article-title":"Forchlorfenuron exposure induces cardiotoxicity via NF-\u03baB\/NLRP3-mediated inflammasome activation independent of Septin2 inhibition","volume":"244","author":"Li","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"115791","DOI":"10.1016\/j.envpol.2020.115791","article-title":"Forchlorfenuron (CPPU) causes disorganization of the cytoskeleton and dysfunction of human umbilical vein endothelial cells, and abnormal vascular development in zebrafish embryos","volume":"271","author":"Gong","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kim, K., Khazan, N., Rowswell-Turner, R.B., Singh, R.K., Moore, T., Strawderman, M.S., Miller, J.P., Snyder, C.W.A., Awada, A., and Moore, R.G. (2024). Forchlorfenuron-Induced Mitochondrial Respiration Inhibition and Metabolic Shifts in Endometrial Cancer. Cancers, 16.","DOI":"10.3390\/cancers16050976"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"114327","DOI":"10.1016\/j.ecoenv.2022.114327","article-title":"Trimethyltin induces apoptosis and necroptosis of mouse liver by oxidative stress through YAP phosphorylation","volume":"248","author":"Wang","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1016\/j.molcel.2024.10.002","article-title":"Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway","volume":"84","author":"Zhang","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/s41568-021-00435-0","article-title":"The role of ROS in tumour development and progression","volume":"22","author":"Cheung","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e2402795","DOI":"10.1002\/advs.202402795","article-title":"MAPK Signaling-Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin-Induced Apoptosis and Ferroptosis","volume":"11","author":"Di","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"157604","DOI":"10.1016\/j.phymed.2025.157604","article-title":"Liquiritin targets NF-\u03baB\/MAPK signaling to attenuate osteoclastogenesis and triggers apoptosis through PPAR\u03b3 activation","volume":"149","author":"Wu","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s12276-025-01390-8","article-title":"Phospholipase C \u03b24 promotes RANKL-dependent osteoclastogenesis by interacting with MKK3 and p38 MAPK","volume":"57","author":"Lee","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102564","DOI":"10.1016\/j.redox.2022.102564","article-title":"Increased ATF2 expression predicts poor prognosis and inhibits sorafenib-induced ferroptosis in gastric cancer","volume":"59","author":"Xu","year":"2022","journal-title":"Redox Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41392-025-02176-0","article-title":"The BCL2 family: From apoptosis mechanisms to new advances in targeted therapy","volume":"10","author":"Vogler","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e179570","DOI":"10.1172\/JCI179570","article-title":"Targeting apoptotic pathways for cancer therapy","volume":"134","author":"Tian","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102886","DOI":"10.1016\/j.redox.2023.102886","article-title":"Nickel induces blood-testis barrier damage through ROS-mediated p38 MAPK pathways in mice","volume":"67","author":"Zeng","year":"2023","journal-title":"Redox Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/s41419-025-07770-2","article-title":"Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: A p53-independent pyroptotic mechanism via ROS\/p-p38\/NOXA\/caspase-3\/GSDME axis","volume":"16","author":"Tang","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1038\/s41418-023-01187-0","article-title":"Identity, structure, and function of the mitochondrial permeability transition pore: Controversies, consensus, recent advances, and future directions","volume":"30","author":"Bernardi","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.chemosphere.2017.09.099","article-title":"The inflammatory responses in Cu-mediated elemental imbalance is associated with mitochondrial fission and intrinsic apoptosis in Gallus gallus heart","volume":"189","author":"Li","year":"2017","journal-title":"Chemosphere"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s11658-024-00631-4","article-title":"Paeoniflorin protects hepatocytes from APAP-induced damage through launching autophagy via the MAPK\/mTOR signaling pathway","volume":"29","author":"Deng","year":"2024","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.7150\/ijbs.97362","article-title":"Catalpol attenuates hepatic glucose metabolism disorder and oxidative stress in triptolide-induced liver injury by regulating the SIRT1\/HIF-1\u03b1 pathway","volume":"20","author":"Nie","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.fsi.2020.06.031","article-title":"Zinc exerts its renal protection effect on arsenic-exposed common carp: A signaling network comprising Nrf2, NF-\u03baB and MAPK pathways","volume":"104","author":"Wang","year":"2020","journal-title":"Fish. Shellfish Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"102926","DOI":"10.1016\/j.redox.2023.102926","article-title":"Mitochondrial complex I ROS production and redox signaling in hypoxia","volume":"67","author":"Okoye","year":"2023","journal-title":"Redox Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.actbio.2025.07.004","article-title":"Mitochondria-targeted ROS-scavenging polymer protects the hepatocytes and macrophages against hepatic ischemia-reperfusion injury","volume":"202","author":"Hu","year":"2025","journal-title":"Acta Biomater."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103859","DOI":"10.1016\/j.redox.2025.103859","article-title":"Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond","volume":"86","author":"Wojtovich","year":"2025","journal-title":"Redox Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Liao, Y., Ding, Y., Yu, L., Xiang, C., and Yang, M. (2022). Exploring the mechanism of Alisma orientale for the treatment of pregnancy induced hypertension and potential hepato-nephrotoxicity by using network pharmacology, network toxicology, molecular docking and molecular dynamics simulation. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1027112"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2173\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T09:39:01Z","timestamp":1772098741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":27,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27052173"],"URL":"https:\/\/doi.org\/10.3390\/ijms27052173","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,26]]}}}