Disruption of the eEF1A1/ARID3A/PKC‐δ Complex by Neferine Inhibits Macrophage Glycolytic Reprogramming in Atherosclerosis
Abstract Glycolytic reprogramming of macrophages is a decisive factor in atherosclerosis (AS) plaque formation. Eukaryotic elongation factor 1A1 (eEF1A1) plays an important role in protein synthesis, ubiquitination degradation, and nuclear translocation. However, the potential function of eEF1A1 in...
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202416158 |
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| author | Baoping Xie Li‐Wen Tian Chenxu Liu Jiahua Li Xiaoyu Tian Rong Zhang Fan Zhang Zhongqiu Liu Yuanyuan Cheng |
| author_facet | Baoping Xie Li‐Wen Tian Chenxu Liu Jiahua Li Xiaoyu Tian Rong Zhang Fan Zhang Zhongqiu Liu Yuanyuan Cheng |
| author_sort | Baoping Xie |
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| description | Abstract Glycolytic reprogramming of macrophages is a decisive factor in atherosclerosis (AS) plaque formation. Eukaryotic elongation factor 1A1 (eEF1A1) plays an important role in protein synthesis, ubiquitination degradation, and nuclear translocation. However, the potential function of eEF1A1 in AS has not yet been fully understood. Here, the natural small molecule neferine (Nef), which targets eEF1A1 to suppress macrophage glycolytic reprogramming is discovered. In this work, chemical genetics and non‐modified target confirmation assays are used to confirm that eEF1A1 is a direct target of Nef. Mechanically, Nef disrupted the formation of the eEF1A1/ARID3A/PKC‐δ complex, inhibits phosphorylation of ARID3A at Thr491, and consequently prevents its nuclear translocation. Meanwhile, it is verified that ARID3A is a transcriptional regulator of enolase 2 (ENO2), an important enzyme in the glycolytic process. Nef suppresses ENO2 transcription activation by affecting ARID3A binding to the promoter region of ENO2, which results in macrophage glycolytic reprogramming inhibition and transformation of macrophages from M1 to M2. Collectively, these findings provide an attractive future direction for AS therapy by inhibiting ARID3A/ENO2‐mediated macrophage glycolytic reprogramming by targeting eEF1A1. |
| format | Article |
| id | doaj-art-41873c7718bc4b95b76b972bde1c6a96 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
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| spelling | doaj-art-41873c7718bc4b95b76b972bde1c6a962025-08-20T02:17:28ZengWileyAdvanced Science2198-38442025-04-011215n/an/a10.1002/advs.202416158Disruption of the eEF1A1/ARID3A/PKC‐δ Complex by Neferine Inhibits Macrophage Glycolytic Reprogramming in AtherosclerosisBaoping Xie0Li‐Wen Tian1Chenxu Liu2Jiahua Li3Xiaoyu Tian4Rong Zhang5Fan Zhang6Zhongqiu Liu7Yuanyuan Cheng8State Key Laboratory of Traditional Chinese Medicine Syndrome Key Laboratory for Translational Cancer Research of Chinese Medicine Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 ChinaSchool of Pharmaceutical Sciences Southern Medical University Guangzhou 510515 ChinaState Key Laboratory of Traditional Chinese Medicine Syndrome Key Laboratory for Translational Cancer Research of Chinese Medicine Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 ChinaState Key Laboratory of Traditional Chinese Medicine Syndrome Key Laboratory for Translational Cancer Research of Chinese Medicine Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 ChinaState Key Laboratory of Traditional Chinese Medicine Syndrome Key Laboratory for Translational Cancer Research of Chinese Medicine Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 ChinaState Key Laboratory of Traditional Chinese Medicine Syndrome Key Laboratory for Translational Cancer Research of Chinese Medicine Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 ChinaState Key Laboratory of Traditional Chinese Medicine Syndrome Key Laboratory for Translational Cancer Research of Chinese Medicine Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 ChinaState Key Laboratory of Traditional Chinese Medicine Syndrome Key Laboratory for Translational Cancer Research of Chinese Medicine Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 ChinaState Key Laboratory of Traditional Chinese Medicine Syndrome Key Laboratory for Translational Cancer Research of Chinese Medicine Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 ChinaAbstract Glycolytic reprogramming of macrophages is a decisive factor in atherosclerosis (AS) plaque formation. Eukaryotic elongation factor 1A1 (eEF1A1) plays an important role in protein synthesis, ubiquitination degradation, and nuclear translocation. However, the potential function of eEF1A1 in AS has not yet been fully understood. Here, the natural small molecule neferine (Nef), which targets eEF1A1 to suppress macrophage glycolytic reprogramming is discovered. In this work, chemical genetics and non‐modified target confirmation assays are used to confirm that eEF1A1 is a direct target of Nef. Mechanically, Nef disrupted the formation of the eEF1A1/ARID3A/PKC‐δ complex, inhibits phosphorylation of ARID3A at Thr491, and consequently prevents its nuclear translocation. Meanwhile, it is verified that ARID3A is a transcriptional regulator of enolase 2 (ENO2), an important enzyme in the glycolytic process. Nef suppresses ENO2 transcription activation by affecting ARID3A binding to the promoter region of ENO2, which results in macrophage glycolytic reprogramming inhibition and transformation of macrophages from M1 to M2. Collectively, these findings provide an attractive future direction for AS therapy by inhibiting ARID3A/ENO2‐mediated macrophage glycolytic reprogramming by targeting eEF1A1.https://doi.org/10.1002/advs.202416158atherosclerosiseEF1A1/ARID3A/PKC‐δ complexmacrophage glycolytic reprogrammingneferine |
| spellingShingle | Baoping Xie Li‐Wen Tian Chenxu Liu Jiahua Li Xiaoyu Tian Rong Zhang Fan Zhang Zhongqiu Liu Yuanyuan Cheng Disruption of the eEF1A1/ARID3A/PKC‐δ Complex by Neferine Inhibits Macrophage Glycolytic Reprogramming in Atherosclerosis Advanced Science atherosclerosis eEF1A1/ARID3A/PKC‐δ complex macrophage glycolytic reprogramming neferine |
| title | Disruption of the eEF1A1/ARID3A/PKC‐δ Complex by Neferine Inhibits Macrophage Glycolytic Reprogramming in Atherosclerosis |
| title_full | Disruption of the eEF1A1/ARID3A/PKC‐δ Complex by Neferine Inhibits Macrophage Glycolytic Reprogramming in Atherosclerosis |
| title_fullStr | Disruption of the eEF1A1/ARID3A/PKC‐δ Complex by Neferine Inhibits Macrophage Glycolytic Reprogramming in Atherosclerosis |
| title_full_unstemmed | Disruption of the eEF1A1/ARID3A/PKC‐δ Complex by Neferine Inhibits Macrophage Glycolytic Reprogramming in Atherosclerosis |
| title_short | Disruption of the eEF1A1/ARID3A/PKC‐δ Complex by Neferine Inhibits Macrophage Glycolytic Reprogramming in Atherosclerosis |
| title_sort | disruption of the eef1a1 arid3a pkc δ complex by neferine inhibits macrophage glycolytic reprogramming in atherosclerosis |
| topic | atherosclerosis eEF1A1/ARID3A/PKC‐δ complex macrophage glycolytic reprogramming neferine |
| url | https://doi.org/10.1002/advs.202416158 |
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