Nuciferine Attenuates Cancer Cachexia‐Induced Muscle Wasting in Mice via HSP90AA1
ABSTRACT Background Around 80% of patients with advanced cancer have cancer cachexia (CC), a serious complication for which there are currently no FDA‐approved treatments. Nuciferine (NF) is the main active ingredient of lotus leaf, which has anti‐inflammatory, anti‐tumour and other effects. The pur...
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| Format: | Article |
| Language: | English |
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Wiley
2025-04-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
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| Online Access: | https://doi.org/10.1002/jcsm.13777 |
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| author | Xueyan An Lisha Ma Yulan Bai Chaoyue Chen Ji Liu Awaguli Dawuti Kewu Zeng Baoxue Yang Bo Han Abudumijiti Abulizi |
| author_facet | Xueyan An Lisha Ma Yulan Bai Chaoyue Chen Ji Liu Awaguli Dawuti Kewu Zeng Baoxue Yang Bo Han Abudumijiti Abulizi |
| author_sort | Xueyan An |
| collection | DOAJ |
| description | ABSTRACT Background Around 80% of patients with advanced cancer have cancer cachexia (CC), a serious complication for which there are currently no FDA‐approved treatments. Nuciferine (NF) is the main active ingredient of lotus leaf, which has anti‐inflammatory, anti‐tumour and other effects. The purpose of this work was to explore the target and mechanism of NF in preventing cancer cachexia‐induced muscle atrophy. Methods The action of NF against CC‐induced muscle atrophy was determined by constructing an animal model with a series of behavioural tests, H&E staining and related markers. Network pharmacology and molecular docking were used to preliminarily determine the mechanism and targets of NF against CC‐induced muscle atrophy. The mechanisms of NF in treating CC‐induced muscle atrophy were verified by western blotting. Molecular dynamics simulation (MD), drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) were used to validate the key target of NF. Results After 13 days of NF treatment, the reduction of limb grip strength and hanging time in LLC model mice increased by 29.7% and 192.2% (p ≤ 0.01; p ≤ 0.001). Gastrocnemius and quadriceps muscles weight/initial body weight (0.98 ± 0.11 and 1.20 ± 0.17) and cross‐sectional area of muscle fibres (600–1600 μm2) of NF‐treated mice were significantly higher than those of the model group (0.84 ± 0.10, 0.94 ± 0.09, 400–800 μm2, respectively) (p ≤ 0.01; p ≤ 0.01; p ≤ 0.001). NF treatment also decreased the MyHC (myosin heavy chain) degradation and the protein levels of muscle‐specific E3 ubiquitin ligases Atrogin1 and MuRF1 in the model group (p ≤ 0.001; p ≤ 0.01; p ≤ 0.05). Network pharmacology revealed that NF majorly targeted AKT1, TNF and HSP90AA1 to regulate PI3K‐Akt and inflammatory pathways. Molecular docking predicted that NF bound best to HSP90AA1. Mechanism analysis demonstrated that NF regulated NF‐κB and AKT–mTOR pathways for alleviating muscle wasting in tumour bearing mice. The results of MD, DARTS and SPR further confirmed that HSP90AA1 was the direct target of NF. Conclusions Overall, we first discovered that NF retards CC‐induced muscle atrophy by regulating AKT–mTOR and NF‐κB signalling pathways through directly binding HSP90AA1, suggesting that NF may be an effective treatment for cancer cachexia. |
| format | Article |
| id | doaj-art-c7d9c9c6cb1b4e94a6e1ae796abd4b1b |
| institution | DOAJ |
| issn | 2190-5991 2190-6009 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
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| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj-art-c7d9c9c6cb1b4e94a6e1ae796abd4b1b2025-08-20T03:10:42ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092025-04-01162n/an/a10.1002/jcsm.13777Nuciferine Attenuates Cancer Cachexia‐Induced Muscle Wasting in Mice via HSP90AA1Xueyan An0Lisha Ma1Yulan Bai2Chaoyue Chen3Ji Liu4Awaguli Dawuti5Kewu Zeng6Baoxue Yang7Bo Han8Abudumijiti Abulizi9Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaState Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing ChinaKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University Shihezi ChinaABSTRACT Background Around 80% of patients with advanced cancer have cancer cachexia (CC), a serious complication for which there are currently no FDA‐approved treatments. Nuciferine (NF) is the main active ingredient of lotus leaf, which has anti‐inflammatory, anti‐tumour and other effects. The purpose of this work was to explore the target and mechanism of NF in preventing cancer cachexia‐induced muscle atrophy. Methods The action of NF against CC‐induced muscle atrophy was determined by constructing an animal model with a series of behavioural tests, H&E staining and related markers. Network pharmacology and molecular docking were used to preliminarily determine the mechanism and targets of NF against CC‐induced muscle atrophy. The mechanisms of NF in treating CC‐induced muscle atrophy were verified by western blotting. Molecular dynamics simulation (MD), drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) were used to validate the key target of NF. Results After 13 days of NF treatment, the reduction of limb grip strength and hanging time in LLC model mice increased by 29.7% and 192.2% (p ≤ 0.01; p ≤ 0.001). Gastrocnemius and quadriceps muscles weight/initial body weight (0.98 ± 0.11 and 1.20 ± 0.17) and cross‐sectional area of muscle fibres (600–1600 μm2) of NF‐treated mice were significantly higher than those of the model group (0.84 ± 0.10, 0.94 ± 0.09, 400–800 μm2, respectively) (p ≤ 0.01; p ≤ 0.01; p ≤ 0.001). NF treatment also decreased the MyHC (myosin heavy chain) degradation and the protein levels of muscle‐specific E3 ubiquitin ligases Atrogin1 and MuRF1 in the model group (p ≤ 0.001; p ≤ 0.01; p ≤ 0.05). Network pharmacology revealed that NF majorly targeted AKT1, TNF and HSP90AA1 to regulate PI3K‐Akt and inflammatory pathways. Molecular docking predicted that NF bound best to HSP90AA1. Mechanism analysis demonstrated that NF regulated NF‐κB and AKT–mTOR pathways for alleviating muscle wasting in tumour bearing mice. The results of MD, DARTS and SPR further confirmed that HSP90AA1 was the direct target of NF. Conclusions Overall, we first discovered that NF retards CC‐induced muscle atrophy by regulating AKT–mTOR and NF‐κB signalling pathways through directly binding HSP90AA1, suggesting that NF may be an effective treatment for cancer cachexia.https://doi.org/10.1002/jcsm.13777AKT–mTORcancer cachexia, muscle wastingHSP90AA1NF‐κBnuciferine |
| spellingShingle | Xueyan An Lisha Ma Yulan Bai Chaoyue Chen Ji Liu Awaguli Dawuti Kewu Zeng Baoxue Yang Bo Han Abudumijiti Abulizi Nuciferine Attenuates Cancer Cachexia‐Induced Muscle Wasting in Mice via HSP90AA1 Journal of Cachexia, Sarcopenia and Muscle AKT–mTOR cancer cachexia, muscle wasting HSP90AA1 NF‐κB nuciferine |
| title | Nuciferine Attenuates Cancer Cachexia‐Induced Muscle Wasting in Mice via HSP90AA1 |
| title_full | Nuciferine Attenuates Cancer Cachexia‐Induced Muscle Wasting in Mice via HSP90AA1 |
| title_fullStr | Nuciferine Attenuates Cancer Cachexia‐Induced Muscle Wasting in Mice via HSP90AA1 |
| title_full_unstemmed | Nuciferine Attenuates Cancer Cachexia‐Induced Muscle Wasting in Mice via HSP90AA1 |
| title_short | Nuciferine Attenuates Cancer Cachexia‐Induced Muscle Wasting in Mice via HSP90AA1 |
| title_sort | nuciferine attenuates cancer cachexia induced muscle wasting in mice via hsp90aa1 |
| topic | AKT–mTOR cancer cachexia, muscle wasting HSP90AA1 NF‐κB nuciferine |
| url | https://doi.org/10.1002/jcsm.13777 |
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