Integrating network toxicology, transcriptomics, and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in LO2 cells
Okadaic acid (OKA), a potent phycotoxin existed in shellfish, is known to cause liver damage. However, the hepatic mechanisms underlying its toxicity remain poorly understood. In this work, we aim to elucidate the hepatotoxic mechanisms of OKA by integrating network toxicology with transcriptomic an...
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| Format: | Article |
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Elsevier
2025-09-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325009212 |
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| author | Zhiqiang Luo Fulu Pan Huixia Fan Ruofan Guo Jingqi Zheng Shuo Zhang Jiaru Shi Wei Lin Chen Wang Yanli Pan Guohua Yu |
| author_facet | Zhiqiang Luo Fulu Pan Huixia Fan Ruofan Guo Jingqi Zheng Shuo Zhang Jiaru Shi Wei Lin Chen Wang Yanli Pan Guohua Yu |
| author_sort | Zhiqiang Luo |
| collection | DOAJ |
| description | Okadaic acid (OKA), a potent phycotoxin existed in shellfish, is known to cause liver damage. However, the hepatic mechanisms underlying its toxicity remain poorly understood. In this work, we aim to elucidate the hepatotoxic mechanisms of OKA by integrating network toxicology with transcriptomic and metabolomic analyses. The results showed that OKA induced hepatotoxicity through cell cycle arrest and apoptosis in LO2 cells. Both network toxicology and transcriptomic analyses identified the MAPK signaling pathway as highly enriched. Key genes involved in the MAPK pathway, including MAP2K3, MAP3K14, MAP3K8, TNF, IL1A and NFKB2, were validated by qPCR and found to be upregulated. Western blot analysis further revealed that OKA significantly upregulated p-p38 expression, with no significant effect on p-ERK and p-JNK levels. Treatment of LO2 cells with the p38 inhibitor SB203580 mitigated OKA-induced hepatotoxicity, supporting the critical role of p38 MAPK signaling in OKA-mediated hepatotoxicity. Additionally, metabolomic data demonstrated that OKA primarily disrupted metabolic pathways, including cysteine and methionine metabolism, glutathione metabolism, and lipolysis regulation. Further integration of transcriptomics and metabolomics revealed that OKA caused metabolic dysfunction by altering vital metabolites, including diisooctyl phthalate, gamma-glutamylglutamate, and gamma-glutamylglutamine. In summary, these findings provide valuable insights into the mechanisms underlying OKA-induced hepatotoxicity, emphasizing the integration of network toxicology, transcriptomics, and metabolomics as a novel strategy for studying the action modes of biotoxins. |
| format | Article |
| id | doaj-art-4f32ebc098894fdaa4f320c9ad8f35b4 |
| institution | Matheson Library |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-4f32ebc098894fdaa4f320c9ad8f35b42025-06-26T09:51:58ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-01302118576Integrating network toxicology, transcriptomics, and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in LO2 cellsZhiqiang Luo0Fulu Pan1Huixia Fan2Ruofan Guo3Jingqi Zheng4Shuo Zhang5Jiaru Shi6Wei Lin7Chen Wang8Yanli Pan9Guohua Yu10State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaState Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaXiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaInstitute of Information on Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China; Corresponding authors.School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China; Corresponding authors.Okadaic acid (OKA), a potent phycotoxin existed in shellfish, is known to cause liver damage. However, the hepatic mechanisms underlying its toxicity remain poorly understood. In this work, we aim to elucidate the hepatotoxic mechanisms of OKA by integrating network toxicology with transcriptomic and metabolomic analyses. The results showed that OKA induced hepatotoxicity through cell cycle arrest and apoptosis in LO2 cells. Both network toxicology and transcriptomic analyses identified the MAPK signaling pathway as highly enriched. Key genes involved in the MAPK pathway, including MAP2K3, MAP3K14, MAP3K8, TNF, IL1A and NFKB2, were validated by qPCR and found to be upregulated. Western blot analysis further revealed that OKA significantly upregulated p-p38 expression, with no significant effect on p-ERK and p-JNK levels. Treatment of LO2 cells with the p38 inhibitor SB203580 mitigated OKA-induced hepatotoxicity, supporting the critical role of p38 MAPK signaling in OKA-mediated hepatotoxicity. Additionally, metabolomic data demonstrated that OKA primarily disrupted metabolic pathways, including cysteine and methionine metabolism, glutathione metabolism, and lipolysis regulation. Further integration of transcriptomics and metabolomics revealed that OKA caused metabolic dysfunction by altering vital metabolites, including diisooctyl phthalate, gamma-glutamylglutamate, and gamma-glutamylglutamine. In summary, these findings provide valuable insights into the mechanisms underlying OKA-induced hepatotoxicity, emphasizing the integration of network toxicology, transcriptomics, and metabolomics as a novel strategy for studying the action modes of biotoxins.http://www.sciencedirect.com/science/article/pii/S0147651325009212Okadaic acidHepatotoxicityNetwork toxicologyTranscriptomicsMetabolomics |
| spellingShingle | Zhiqiang Luo Fulu Pan Huixia Fan Ruofan Guo Jingqi Zheng Shuo Zhang Jiaru Shi Wei Lin Chen Wang Yanli Pan Guohua Yu Integrating network toxicology, transcriptomics, and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in LO2 cells Ecotoxicology and Environmental Safety Okadaic acid Hepatotoxicity Network toxicology Transcriptomics Metabolomics |
| title | Integrating network toxicology, transcriptomics, and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in LO2 cells |
| title_full | Integrating network toxicology, transcriptomics, and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in LO2 cells |
| title_fullStr | Integrating network toxicology, transcriptomics, and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in LO2 cells |
| title_full_unstemmed | Integrating network toxicology, transcriptomics, and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in LO2 cells |
| title_short | Integrating network toxicology, transcriptomics, and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in LO2 cells |
| title_sort | integrating network toxicology transcriptomics and metabolomics uncovers the hepatotoxic mechanisms of okadaic acid in lo2 cells |
| topic | Okadaic acid Hepatotoxicity Network toxicology Transcriptomics Metabolomics |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325009212 |
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