<i>Euphorbia humifusa</i> Willd. ex Schltdl. Mitigates Liver Injury via KEAP1-NFE2L2-Mediated Ferroptosis Regulation: Network Pharmacology and Experimental Validation
Liver injury poses major health risks in livestock, necessitating effective therapeutic interventions. This study elucidates the hepatoprotective mechanisms of <i>Euphorbia humifusa</i> Willd. ex Schltdl. (EHW) by integrating network pharmacology, molecular docking, and experimental vali...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
|
| Series: | Veterinary Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2306-7381/12/4/350 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850154955664523264 |
|---|---|
| author | Hongxu Du Kunzhao Yang Jingyi Yang Junjie Wan Yu Pan Weijie Song Shuang Xu Cheng Chen Jiahui Li |
| author_facet | Hongxu Du Kunzhao Yang Jingyi Yang Junjie Wan Yu Pan Weijie Song Shuang Xu Cheng Chen Jiahui Li |
| author_sort | Hongxu Du |
| collection | DOAJ |
| description | Liver injury poses major health risks in livestock, necessitating effective therapeutic interventions. This study elucidates the hepatoprotective mechanisms of <i>Euphorbia humifusa</i> Willd. ex Schltdl. (EHW) by integrating network pharmacology, molecular docking, and experimental validation. Using a CCl<sub>4</sub>-induced liver injury model mimicking veterinary clinical scenarios, EHW markedly alleviated hepatic damage, demonstrated by reduced liver index, serum ALT and AST levels, histopathological lesions, iron accumulation, inflammatory cytokines, and ferroptosis-associated gene expression. Network pharmacology identified EHW’s core bioactive components (quercetin, kaempferol, and β-sitosterol) and critical targets (<i>IL-6</i>, <i>STAT3</i>, <i>HIF-1α</i>, <i>PTGS2</i>, <i>NFE2L2</i>, and <i>KEAP1</i>) which were linked to ferroptosis and oxidative stress. Molecular docking revealed robust binding affinities between these compounds and ferroptosis-related proteins. <i>In vivo</i> validation confirmed that EHW inhibited <i>KEAP1</i>, activated <i>NFE2L2</i>-mediated antioxidant defenses (upregulating <i>SOD1</i> and <i>NQO1</i>), restored iron homeostasis (lowering <i>TFR1</i>, elevating <i>FTH1</i>), and attenuated phospholipid peroxidation by suppressing <i>ACSL4</i> and <i>ALOX12</i>. These results indicate that EHW mitigates ferroptosis-driven liver injury via KEAP1-NFE2L2 signaling to restore iron homeostasis and reduce oxidative stress, offering a mechanistic foundation for its clinical application in veterinary hepatoprotection. |
| format | Article |
| id | doaj-art-3cd93ff52449438f892589ccc527db13 |
| institution | OA Journals |
| issn | 2306-7381 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Veterinary Sciences |
| spelling | doaj-art-3cd93ff52449438f892589ccc527db132025-08-20T02:25:07ZengMDPI AGVeterinary Sciences2306-73812025-04-0112435010.3390/vetsci12040350<i>Euphorbia humifusa</i> Willd. ex Schltdl. Mitigates Liver Injury via KEAP1-NFE2L2-Mediated Ferroptosis Regulation: Network Pharmacology and Experimental ValidationHongxu Du0Kunzhao Yang1Jingyi Yang2Junjie Wan3Yu Pan4Weijie Song5Shuang Xu6Cheng Chen7Jiahui Li8Department of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaDepartment of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaDepartment of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaDepartment of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaDepartment of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaDepartment of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaDepartment of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaDepartment of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaDepartment of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, ChinaLiver injury poses major health risks in livestock, necessitating effective therapeutic interventions. This study elucidates the hepatoprotective mechanisms of <i>Euphorbia humifusa</i> Willd. ex Schltdl. (EHW) by integrating network pharmacology, molecular docking, and experimental validation. Using a CCl<sub>4</sub>-induced liver injury model mimicking veterinary clinical scenarios, EHW markedly alleviated hepatic damage, demonstrated by reduced liver index, serum ALT and AST levels, histopathological lesions, iron accumulation, inflammatory cytokines, and ferroptosis-associated gene expression. Network pharmacology identified EHW’s core bioactive components (quercetin, kaempferol, and β-sitosterol) and critical targets (<i>IL-6</i>, <i>STAT3</i>, <i>HIF-1α</i>, <i>PTGS2</i>, <i>NFE2L2</i>, and <i>KEAP1</i>) which were linked to ferroptosis and oxidative stress. Molecular docking revealed robust binding affinities between these compounds and ferroptosis-related proteins. <i>In vivo</i> validation confirmed that EHW inhibited <i>KEAP1</i>, activated <i>NFE2L2</i>-mediated antioxidant defenses (upregulating <i>SOD1</i> and <i>NQO1</i>), restored iron homeostasis (lowering <i>TFR1</i>, elevating <i>FTH1</i>), and attenuated phospholipid peroxidation by suppressing <i>ACSL4</i> and <i>ALOX12</i>. These results indicate that EHW mitigates ferroptosis-driven liver injury via KEAP1-NFE2L2 signaling to restore iron homeostasis and reduce oxidative stress, offering a mechanistic foundation for its clinical application in veterinary hepatoprotection.https://www.mdpi.com/2306-7381/12/4/350<i>Euphorbia humifusa</i> Willd. ex Schltdl.hepatic injuryferroptosisnetwork pharmacology |
| spellingShingle | Hongxu Du Kunzhao Yang Jingyi Yang Junjie Wan Yu Pan Weijie Song Shuang Xu Cheng Chen Jiahui Li <i>Euphorbia humifusa</i> Willd. ex Schltdl. Mitigates Liver Injury via KEAP1-NFE2L2-Mediated Ferroptosis Regulation: Network Pharmacology and Experimental Validation Veterinary Sciences <i>Euphorbia humifusa</i> Willd. ex Schltdl. hepatic injury ferroptosis network pharmacology |
| title | <i>Euphorbia humifusa</i> Willd. ex Schltdl. Mitigates Liver Injury via KEAP1-NFE2L2-Mediated Ferroptosis Regulation: Network Pharmacology and Experimental Validation |
| title_full | <i>Euphorbia humifusa</i> Willd. ex Schltdl. Mitigates Liver Injury via KEAP1-NFE2L2-Mediated Ferroptosis Regulation: Network Pharmacology and Experimental Validation |
| title_fullStr | <i>Euphorbia humifusa</i> Willd. ex Schltdl. Mitigates Liver Injury via KEAP1-NFE2L2-Mediated Ferroptosis Regulation: Network Pharmacology and Experimental Validation |
| title_full_unstemmed | <i>Euphorbia humifusa</i> Willd. ex Schltdl. Mitigates Liver Injury via KEAP1-NFE2L2-Mediated Ferroptosis Regulation: Network Pharmacology and Experimental Validation |
| title_short | <i>Euphorbia humifusa</i> Willd. ex Schltdl. Mitigates Liver Injury via KEAP1-NFE2L2-Mediated Ferroptosis Regulation: Network Pharmacology and Experimental Validation |
| title_sort | i euphorbia humifusa i willd ex schltdl mitigates liver injury via keap1 nfe2l2 mediated ferroptosis regulation network pharmacology and experimental validation |
| topic | <i>Euphorbia humifusa</i> Willd. ex Schltdl. hepatic injury ferroptosis network pharmacology |
| url | https://www.mdpi.com/2306-7381/12/4/350 |
| work_keys_str_mv | AT hongxudu ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation AT kunzhaoyang ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation AT jingyiyang ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation AT junjiewan ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation AT yupan ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation AT weijiesong ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation AT shuangxu ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation AT chengchen ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation AT jiahuili ieuphorbiahumifusaiwilldexschltdlmitigatesliverinjuryviakeap1nfe2l2mediatedferroptosisregulationnetworkpharmacologyandexperimentalvalidation |