AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease
Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking...
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Elsevier
2025-02-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000428 |
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| author | Lulu Zhang Yi Zheng Mingyan Shao Aiping Chen Meiyi Liu Wenlong Sun Tianxing Li Yini Fang Yang Dong Shipeng Zhao Hui Luo Juan Feng Qi Wang Lingru Li Yanfei Zheng |
| author_facet | Lulu Zhang Yi Zheng Mingyan Shao Aiping Chen Meiyi Liu Wenlong Sun Tianxing Li Yini Fang Yang Dong Shipeng Zhao Hui Luo Juan Feng Qi Wang Lingru Li Yanfei Zheng |
| author_sort | Lulu Zhang |
| collection | DOAJ |
| description | Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF’s effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. In vivo, QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF’s mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5‘-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. In vitro, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis. |
| format | Article |
| id | doaj-art-d4046498ab1646fda77d0cc0aa34dfb4 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-d4046498ab1646fda77d0cc0aa34dfb42025-02-08T04:59:52ZengElsevierPharmacological Research1096-11862025-02-01212107617AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver diseaseLulu Zhang0Yi Zheng1Mingyan Shao2Aiping Chen3Meiyi Liu4Wenlong Sun5Tianxing Li6Yini Fang7Yang Dong8Shipeng Zhao9Hui Luo10Juan Feng11Qi Wang12Lingru Li13Yanfei Zheng14National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, ChinaNational Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, ChinaNational Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, ChinaSchool of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, ChinaNational Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, ChinaInstitute of Biomedical Research, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255000, ChinaNational Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, ChinaNational Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, ChinaMonitoning and Statistical Research Center, National Administration of Traditional Chinese Medicine, Beijing 100600, ChinaGraduate School of China Academy of Chinese Medical Sciences, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaNational Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, ChinaCollege of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen 518118, China; Correspondence to: College of Health Science and Environmental Engineering, Shenzhen Technology University, No. 3002, Lantian Road, Pingshan District, Shenzhen 518118, China.National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; Correspondence to: National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, NO.11, Beisanhuan East Road, Chaoyang District, Beijing 100029, China.National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; Correspondence to: National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, NO.11, Beisanhuan East Road, Chaoyang District, Beijing 100029, China.National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; Correspondence to: National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, NO.11, Beisanhuan East Road, Chaoyang District, Beijing 100029, China.Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF’s effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. In vivo, QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF’s mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5‘-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. In vitro, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.http://www.sciencedirect.com/science/article/pii/S1043661825000428MAFLDQigui Jiangzhi FormulaAutophagyAMPK/SIRT1-TFEBAlphaFold |
| spellingShingle | Lulu Zhang Yi Zheng Mingyan Shao Aiping Chen Meiyi Liu Wenlong Sun Tianxing Li Yini Fang Yang Dong Shipeng Zhao Hui Luo Juan Feng Qi Wang Lingru Li Yanfei Zheng AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease Pharmacological Research MAFLD Qigui Jiangzhi Formula Autophagy AMPK/SIRT1-TFEB AlphaFold |
| title | AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease |
| title_full | AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease |
| title_fullStr | AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease |
| title_full_unstemmed | AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease |
| title_short | AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease |
| title_sort | alphafold based ai docking reveals ampk sirt1 tfeb pathway modulation by traditional chinese medicine in metabolic associated fatty liver disease |
| topic | MAFLD Qigui Jiangzhi Formula Autophagy AMPK/SIRT1-TFEB AlphaFold |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000428 |
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