20-Hydroxyecdysone inhibits inflammation via SIRT6-mediated NF-κB signaling in endothelial cells
Open accessAbstract
20-Hydroxyecdysone (20E) is known to have numerous pharmacological activities and can be used to treat diabetes and cardiovascular diseases. However, the protective effects of 20E against endothelial dysfunction and its targets remain unclear. In the present study, we revealed that 20E treatment could modulate the release of the endothelium-derived vasomotor factors NO, PGI2 and ET-1 and suppress the expression of ACE in TNF-α-induced 3D-cultured HUVECs. In addition, 20E suppressed the expression of CD40 and promoted the expression of SIRT6 in TNF-α-induced 3D-cultured HUVECs. The cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular docking results demonstrated that 20E binding increased SIRT6 stability, indicating that 20E directly bound to SIRT6 in HUVECs. Further investigation of the underlying mechanism showed that 20E could upregulate SIRT6 levels and that SIRT6 knockdown abolished the regulatory effect of 20E on CD40 in TNF-α-induced HUVECs, while SIRT6 overexpression further improved the effect of 20E. Moreover, we found that 20E could reduce the acetylation of NF-κB p65 (K310) through SIRT6, but the catalytic inactive mutant SIRT6 (H133Y) did not promote the deacetylation of NF-κB p65, suggesting that the inhibitory effect of 20E on NF-κB p65 was dependent on SIRT6 deacetylase activity. Additionally, our results indicated that 20E inhibited NF-κB via SIRT6, and the expression of CD40 was increased in HUVECs treated with SIRT6 siRNA and NF-κB inhibitor. In conclusion, the present study demonstrates that 20E exerts its effect through SIRT6-mediated deacetylation of NF-κB p65 (K310) to inhibit CD40 expression in ECs, and 20E may have therapeutic potential for the treatment of cardiovascular diseases.
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20E exerts its effect through SIRT6-mediated deacetylation of NF-κB p65 to inhibit CD40 expression in 3-D human endothelial cell culture (HUVEC).
“Recently, it has been shown that 20E exerts its effect through SIRT6-mediated deacetylation of NF-κB p65 (nuclear factor kappa of B cells) to inhibit CD40 expression in 3-D human endothelial cell culture (HUVEC).”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [13]
Within the in vitro studies of ecdysterone, no serious effects were reported.
“Within these studies, no serious effects were reported [52,53,54,55,56,57,58,60,61,62,63,64,65,66,67,68,69,70,71,72,73].”
From Ecdysterone and Turkesterone—Compounds with Prominent Potential in Sport and Healthy Nutrition (2024) · cites this paper as [57]
In vitro studies associate ecdysterone with endothelial dysfunction prevention, osteoporosis prevention, glucose regulation, cytotoxic effects, antibacterial properties, immunomodulatory effects, and anti-inflammatory activities.
“Moreover, the effects on cell lines are associated with endothelial dysfunction prevention, osteoporosis prevention, glucose regulation, cytotoxic effects, antibacterial properties, immunomodulatory effects, and anti-inflammatory activities [52,53,54,55,56,57,58,60,61,62,63,64,65,66,67,68,69,70,71,72,73].”
From Ecdysterone and Turkesterone—Compounds with Prominent Potential in Sport and Healthy Nutrition (2024) · cites this paper as [57]
This scenario protects against endothelial inflammation and is similar to the anti-inflammatory feature exerted by some calorie restriction mimetics, like metformin, curcumin, and alpha-ketoglutarate.
“This scenario protects against endothelial inflammation [13] and is similar to the anti-inflammatory feature exerted by some CRMs, like metformin, curcumin, and alpha-ketoglutarate [58].”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [13]
According to in vitro assays, 20E could bind to Sirt6 directly and stimulate its activity, suggesting a starting point for this mechanism.
“According to in vitro assays, 20E could bind to Sirt6 directly and stimulate its activity, suggesting a starting point for this mechanism.”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [13]
In docking experiments, 20E binds to Sirt6 and stimulates its expression and stabilizes it in HUVECs.
“In docking experiments, 20E binds to Sirt6 and stimulates its expression and also stabilizes it in HUVECs.”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [13]
Cites
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Molina, D. M., Jafari, R., Ignatushchenko, M., Seki, T., Larsson, E. A., Dan, C., Sreekumar, L., Cao, Y., & Nordlund, P. (2013) · Science · doi:10.1126/science.1233606 · Cited by 2,261 · see citing works
Target identification using drug affinity responsive target stability (DARTS)
Lomenick, B., Hao, R., Jonai, N., Chin, R., Aghajan, M., Warburton, S., Wang, J., Wu, R. P., Gómez, F., Loo, J. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910040106 · Cited by 1,113 · see citing works
Self-citationSIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L. A., Barrett, J. C., et al. (2008) · Nature · doi:10.1038/nature06736 · Cited by 1,111 · see citing works
Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF‐κB
Chen, L., Mu, Y., & Greene, W. C. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf660 · Cited by 827 · see citing works
Functional and Biomimetic Materials for Engineering of the Three-Dimensional Cell Microenvironment
Huang, G., Li, F., Zhao, X., Ma, Y., Li, Y., Lin, M., Jin, G., Lu, T. J., Genin, G. M., & Xu, F. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00094 · Cited by 825 · see citing works
Mechanisms of NF-κB p65 and strategies for therapeutic manipulation
Giridharan, S., & Srinivasan, M. (2018) · Journal of Inflammation Research · doi:10.2147/jir.s140188 · Cited by 686 · see citing works
SIRT6, a Mammalian Deacylase with Multitasking Abilities
Chang, A. R., Ferrer, C. M., & Mostoslavsky, R. (2019) · Physiological Reviews · doi:10.1152/physrev.00030.2018 · Cited by 236 · see citing works
SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence
Figueras, A. C., Uryga, A., Walters, G., & Erusalimsky, J. D. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs352 · Cited by 182 · see citing works
Qin, H., Wilson, C. A., Lee, S. J., Zhao, X., & Benveniste, E. N. (2005) · Blood · doi:10.1182/blood-2005-02-0759 · Cited by 175 · see citing works
SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions
Bhardwaj, A., & Das, S. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520045113 · Cited by 154 · see citing works
Guo, J., Wang, Z., Wu, J., Liu, M., Li, M., Sun, Y., Huang, W. C., Li, Y., Zhang, Y., Tang, W., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.314032 · Cited by 152 · see citing works
Functional Interplay between Acetylation and Methylation of the RelA Subunit of NF-κB
Yang, X., Tajkhorshid, E., & Chen, L. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01343-09 · Cited by 143 · see citing works
Lin, R., Wang, W., Liu, J., Yang, G., & Han, C. (2006) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2006.05.004 · Cited by 114 · see citing works
Self-citationCalorie restriction-induced SIRT6 activation delays aging by suppressing NF-κB signaling
Zhang, N., Li, Z., Mu, W., Li, L., Liang, Y., Lu, M., Wang, Z., Qiu, Y., & Wang, Z. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1152427 · Cited by 110 · see citing works
Dinan, L., Dioh, W., Veillet, S., & Lafont, R. (2021) · Biomedicines · doi:10.3390/biomedicines9050492 · Cited by 99 · see citing works
Negative regulation of NLRP3 inflammasome by SIRT1 in vascular endothelial cells
Li, Y., Yang, X., He, Y., Wang, W., Zhang, J., Zhang, W., Jing, T., Wang, B., & Lin, R. (2016) · Immunobiology · doi:10.1016/j.imbio.2016.11.002 · Cited by 97 · see citing works
Self-citationModeling Cardiovascular Diseases with hiPSC-Derived Cardiomyocytes in 2D and 3D Cultures
Sacchetto, C., Vitiello, L., de Windt, L. J., Rampazzo, A., & Calore, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093404 · Cited by 91 · see citing works
Sun, H., Wu, Y., Fu, D., Liu, Y., & Huang, C. (2014) · Stem Cells · doi:10.1002/stem.1671 · Cited by 89 · see citing works
Identifying the functional contribution of the defatty-acylase activity of SIRT6
Zhang, X., Khan, S., Jiang, H. X., Antonyak, M. A., Chen, X., Spiegelman, N. A., Shrimp, J. H., Cerione, R. A., & Lin, H. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2106 · Cited by 88 · see citing works
Patten, G. S., Abeywardena, M. Y., & Bennett, L. E. (2013) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2011.651176 · Cited by 68 · see citing works
The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting DDB2
Geng, A.-K., Tang, H.-Y., Huang, J., Qian, Z., Qin, N., Yao, Y., Xu, Z., Chen, H., Lan, L., Xie, H., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa661 · Cited by 61 · see citing works
Shang, J., Zhu, Z., Chen, Y., Song, J., Huang, Y., Song, K., Zhong, J., Xu, X., Wei, J., Wang, C., et al. (2020) · Theranostics · doi:10.7150/thno.44043 · Cited by 55 · see citing works
Lin, R., Liu, J.-T., Gan, W., & Yang, G. (2004) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.27.1537 · Cited by 52 · see citing works
Self-citation20-Hydroxyecdysone activates the protective arm of the RAAS via the MAS receptor
Lafont, R., Serova, M., Didry-Barca, B., Raynal, S., Guibout, L., Dinan, L., Veillet, S., Latil, M., Dioh, W., & Dilda, P. J. (2022) · Journal of Molecular Endocrinology · doi:10.1530/jme-21-0033 · Cited by 50 · see citing works
Sirtuin 6: A potential therapeutic target for cardiovascular diseases
Xie, S., Deng, W., & Qizhu, T. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105214 · Cited by 47 · see citing works
Yao, F., Jin, Z., Lv, X., Zheng, Z., Gao, H., Deng, Y. J., Liu, Y., Chen, L., Wang, W., He, J., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.656272 · Cited by 30 · see citing works
Self-citationWang, B., Chen, R., Gao, H., Lv, X., Chen, L., Wang, W., Liu, Y., Zheng, N., & Lin, R. (2020) · Biomedical Materials · doi:10.1088/1748-605x/ab95e3 · Cited by 28 · see citing works
Self-citationLin, H., Du, Q., Li, Q., Wang, O., Wang, Z., Sahu, N., Elowsky, C. G., Liu, K., Zhang, C., Chung, S., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.07.001 · Cited by 27 · see citing works
Kim, J. J., Hou, L., Yang, G., Mezak, N. P., Wanjare, M., Joubert, L., & Huang, N. F. (2017) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-017-0502-y · Cited by 26 · see citing works
Diosmin restores the skin barrier by targeting the aryl hydrocarbon receptor in atopic dermatitis
Lee, J., Song, K., & Jung, C. H. (2020) · Phytomedicine · doi:10.1016/j.phymed.2020.153418 · Cited by 26 · see citing works
SIRT6 Through the Brain Evolution, Development, and Aging
García-Venzor, A., & Toiber, D. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.747989 · Cited by 26 · see citing works
Gualtero, D. F., Lafaurie, G. I., & Fontanilla, M. R. (2017) · Molecular Oral Microbiology · doi:10.1111/omi.12201 · Cited by 24 · see citing works
Gelatin-based perfusable, endothelial carotid artery model for the study of atherosclerosis
Chen, R., Wang, B., Liu, Y., He, J., Lin, R., & Li, D. (2019) · BioMedical Engineering OnLine · doi:10.1186/s12938-019-0706-6 · Cited by 19 · see citing works
Self-citationWang, Z., Zuo, F., Liu, Q., Wu, X., Du, Q., Lei, Y., Wu, Z.-M., & Lin, H. (2021) · ACS Omega · doi:10.1021/acsomega.0c06187 · Cited by 19 · see citing works
Lin, R., Liu, J., Peng, N., Gan, W., Wang, W., Han, C., & Ding, C. (2006) · Current Neurovascular Research · doi:10.2174/156720206775541796 · Cited by 17 · see citing works
Self-citationZheng, Z., Wang, B., Lv, X., Yao, F., Gao, H., Jin, Z., Liu, Y., Deng, Y. J., Chen, D., Ning, X., et al. (2021) · Experimental Cell Research · doi:10.1016/j.yexcr.2021.112526 · Cited by 17 · see citing works
Self-citationKim, T. Y., Ji, E. S., Lee, J. Y., Kim, J. Y., Yoo, J. S., Szász, A. M., Döme, B., Marko‐Varga, G., & Kwon, H. J. (2020) · Cancers · doi:10.3390/cancers12092613 · Cited by 11 · see citing works
Korkach, I. P., Kotsiuruba, A. V., Prysiazhna, O. D., Ld, M., & Vf, S. (2007) · PubMed · Cited by 9 · see citing works
Thoms, S., Ali, A. I., Jonczyk, R., Scheper, T. H., & Blume, C. A. (2018) · Toxicology in Vitro · doi:10.1016/j.tiv.2018.07.017 · Cited by 9 · see citing works
Camelo, S., Latil, M., Agus, S., Dioh, W., Veillet, S., Lafont, R., & Dilda, P. J. (2021) · Emerging Microbes & Infections · doi:10.1080/22221751.2021.2006579 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Wang, J., Luo, J., Rotili, D., Mai, A., Steegborn, C., Xu, S., & Jin, Z. G. (2023) · Inflammation · doi:10.1007/s10753-023-01911-5 · Cited by 159 · see citing works
Self-citationLin, S., Chang, C.-L., Liou, K., Kao, Y.-K., Wang, Y., Chang, C.-C., Kuo, T. B. J., Huang, H., Yang, C. C. H., Liaw, C., et al. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117097 · Cited by 51 · see citing works
Metabolic mechanisms orchestrated by Sirtuin family to modulate inflammatory responses
Li, X., Li, Y., Hao, Q., Jin, J., & Wang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1448535 · Cited by 35 · see citing works
Ecdysterone and Turkesterone—Compounds with Prominent Potential in Sport and Healthy Nutrition
Todorova, V., Ivanova, S., Chakarov, D., Kraev, K., & Ivanov, K. (2024) · Nutrients · doi:10.3390/nu16091382 · Cited by 31 · see citing works
“[57] Effect of glucocorticoids in osteoblasts and the role of 20HE in the pathogenesis of glucocorticoid-induced osteoporosis.”
BackgroundYang, P.-L., Rong, X.-L., Gao, Z., Wang, J.-J., & Liu, Z. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107588 · Cited by 29 · see citing works
Self-citationAnti-Adipogenic Activity of Rhaponticum carthamoides and Its Secondary Metabolites
Todorova, V., Savova, M. S., Ivanova, S., Ivanov, K., & Georgiev, M. I. (2023) · Nutrients · doi:10.3390/nu15133061 · Cited by 12 · see citing works
Zádor, E. (2025) · Cells · doi:10.3390/cells14060431 · Cited by 9 · see citing works
“Therefore, the authors Therefore, the authors proposed that 20E may have therapeutic potential for the treatment of cardiovascular diseases [13]. proposed that 20E may have therapeutic potential for the treatment of cardiovascular diseases [13].”
Guo, X., Qin, Y., Feng, Z., Li, H., Yang, J., Su, K., Mao, R., & Li, J. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e35307 · Cited by 9 · see citing works
Self-citationWang, Z., Wu, F., Ju, Y., Liang, L., Chang, F.-J., Dong, M., Diao, J., & Wu, H.-Y. (2025) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70446 · Cited by 9 · see citing works
Aksoy, F., Savran, M., Uysal, D., Bağcı, A., İLHAN, İ. İ., İmeci, O. B., Sevük, M. A., Ozmen, O., Tepebaşı, M. Y., & Asci, H. (2026) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000001806 · Cited by 5 · see citing works
Shi, S., Zhang, Y., Zhang, L.-Q., Li, Y., Zhou, X., & Li, R. (2024) · International Urology and Nephrology · doi:10.1007/s11255-024-03970-5 · Cited by 4 · see citing works
Chen, D., Yang, J., Ren, L., Zheng, Z., Jin, Z., Wen, J., He, J., Ding, R., Wang, J., Lin, R., et al. (2024) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-024-03591-w · Cited by 2 · see citing works
Self-citationSemenova, A. A., Igoshkina, A. D., Cherepanova, A. A., Mikina, N. V., Stepanova, A. E., Krasnoshchekova, O. E., Sharapov, V. A., Савченко, Р. Г., Parfenova, L. V., & Dubinin, M. V. (2025) · Biocell · doi:10.32604/biocell.2025.061798 · Cited by 1 · see citing works
Guo, X., Qin, Y., Feng, Z., Yang, J., Li, H., & Li, J. (2023) · doi:10.22541/au.169173437.71611088/v1
Self-citationKılıçcıoğlu, İ., Dülger, G., & Dülger, B. (2025) · Online Türk Sağlık Bilimleri Dergisi · doi:10.26453/otjhs.1685503
Nagalingam, M., & Kathiravan, M. K. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152872
Wu, Z., Wei, Y., Lv, C., Yan, X., Luo, Y., & Liao, H. (2026) · ACS Omega · doi:10.1021/acsomega.5c11972
Wu, S., Jia, W., Hua, J., Jian, J., Zhu, L., Jiang, S., Xiong, A., Li, J., 季丽丽, Liu, W., et al. (2026) · Journal of Separation Science · doi:10.1002/jssc.70481
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Han, Q., Zhang, Y., Feng, J., Zhou, B., Yin, C., & Wu, J. (2026) · Scientific Reports · doi:10.1038/s41598-026-65080-9
- Authors
- Jin, Z., Wang, B., Ren, L., Yang, J., Zheng, Z., Yao, F., Ding, R., Wang, J., He, J., Wang, W., Nan, G., & Lin, R.
- Affiliations
- Xi'an Jiaotong University (CN)
- Corresponding author
- Nan, Guanjun
- Lin, Rong
- ORCID
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2023-06
- Volume
- 1870
- Issue
- 5
- Pages
- 119460
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W4328103627
- Semantic Scholar
- 8db1266f09d8d4e45d79a013686abb27ceafb66d
- Cited by
- 18
- References
- 40
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 4
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81970369)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- 20-hydroxyecdysone, SIRT6, NF-κB signaling, endothelial dysfunction, CD40, TNF-α, human umbilical vein endothelial cells, inflammation, ecdysteroids, cardiovascular disease, nitric oxide, prostacyclin, endothelin-1, ACE
- MeSH terms
- Cardiovascular Diseases, Ecdysterone, Humans, Inflammation, Tumor Necrosis Factor-alpha, NF-kappa B, Sirtuins, Endothelial Cells, Molecular Docking Simulation
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