Salvianolic Acid A Inhibits Ferroptosis in Endothelial Cells and the Progression of Atherosclerosis by Augmenting the Mitochondrial Homeostasis Pathway Associated With Adiponectin Receptor 1.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος:	Salvianolic Acid A Inhibits Ferroptosis in Endothelial Cells and the Progression of Atherosclerosis by Augmenting the Mitochondrial Homeostasis Pathway Associated With Adiponectin Receptor 1.
Συγγραφείς:	Zhu J; The Third Affiliated Hospital of Zhejiang Chinese Medical University (Zhongshan Hospital of Zhejiang Province), Hangzhou, China.; Lipid Metabolism Institute (Molecular Medicine Institute), Zhejiang Chinese Medical University, Hangzhou, China., Guo J; Lipid Metabolism Institute (Molecular Medicine Institute), Zhejiang Chinese Medical University, Hangzhou, China.; School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Liu J; Lipid Metabolism Institute (Molecular Medicine Institute), Zhejiang Chinese Medical University, Hangzhou, China.; School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Chen C; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China., Chen H; Lipid Metabolism Institute (Molecular Medicine Institute), Zhejiang Chinese Medical University, Hangzhou, China.; School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Wang C; Lipid Metabolism Institute (Molecular Medicine Institute), Zhejiang Chinese Medical University, Hangzhou, China.; School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Yuan A; Lipid Metabolism Institute (Molecular Medicine Institute), Zhejiang Chinese Medical University, Hangzhou, China.; School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Lu D; Lipid Metabolism Institute (Molecular Medicine Institute), Zhejiang Chinese Medical University, Hangzhou, China.; School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Le Y; Lipid Metabolism Institute (Molecular Medicine Institute), Zhejiang Chinese Medical University, Hangzhou, China.; School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
Πηγή:	Phytotherapy research : PTR [Phytother Res] 2026 Oct; Vol. 40 (10), pp. 5831-5852. Date of Electronic Publication: 2026 Jul 17.
Τύπος έκδοσης:	Journal Article
Γλώσσα:	English
Στοιχεία περιοδικού:	Publisher: Wiley Country of Publication: England NLM ID: 8904486 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1099-1573 (Electronic) Linking ISSN: 0951418X NLM ISO Abbreviation: Phytother Res Subsets: MEDLINE
Imprint Name(s):	Publication: : Chichester : Wiley Original Publication: London : Heyden & Son, c1987-
Ιατρικοί όροι (MeSH):	Ferroptosis/drug effects , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Caffeic Acids/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Lactates/pharmacology , Receptors, Adiponectin/metabolism, Human Umbilical Vein Endothelial Cells/drug effects ; Reactive Oxygen Species/metabolism ; Homeostasis/drug effects ; Signal Transduction/drug effects ; Lipid Peroxidation/drug effects ; AMP-Activated Protein Kinases/metabolism ; Animals ; Humans ; Mice ; Male ; Mice, Inbred C57BL ; Mice, Knockout, ApoE
Περίληψη:	Endothelial cell ferroptosis drives atherosclerosis. Salvianolic acid A (SAA), a polyphenol from Salvia species, was tested for its ability to inhibit ferroptosis and attenuate atherosclerosis, and its molecular mechanism was investigated. Screening of 124 natural compounds identified SAA as the most potent inhibitor of RSL3-induced ferroptosis in human umbilical vein endothelial cells (HUVECs). Cellular/mitochondrial lipid peroxidation, Fe²⁺ content, ROS, and mitochondrial function were assessed with or without SAA. AMPK signaling was probed using pharmacological inhibitors. The AdipoR1 axis was examined via siRNA knockdown. In vivo, ApoE^-/- mice on a Western diet were treated with SAA to evaluate atherosclerosis and ferroptotic damage. SAA was identified as the most potent inhibitor of (1S,3R)-RSL3-induced ferroptosis in HUVECs among the screened natural compounds. SAA inhibited the ferroptotic response by restoring GPX4-dependent antioxidant capacity and preventing lipid peroxidation at both the cellular and mitochondrial levels. It improved mitochondrial function by restoring homeostasis of the mitochondrial quality control system, inhibiting mitochondrial reactive oxygen species generation, reducing ferrous iron accumulation, limiting mitochondrial lipid peroxidation, and preserving mitochondrial ultrastructure. The protective effects of SAA against ferroptosis were abolished by AMPK inhibitors, which disrupted cellular lipid metabolism and mitochondrial function regulation. The deleterious effects of AMPK inhibition were reversed by co-treatment with the mitochondrial reactive oxygen species inhibitor MitoTempol. Knockdown of AdipoR1 and experiments with the AMPK agonist AICAR confirmed that salvianolic acid A restores mitochondrial homeostasis and inhibits ferroptosis specifically through activation of the AdipoR1-AMPK signaling pathway. In vivo, treatment with SAA significantly ameliorated Western diet-induced atherosclerosis and ferroptosis-like cell damage in ApoE^-/- mice. SAA has strong therapeutic potential against endothelial ferroptosis and atherosclerosis by restoring mitochondrial homeostasis through AdipoR1-AMPK pathway activation. These findings support further clinical investigation of SAA for treating atherosclerosis and other endothelium-related cardiovascular diseases. (© 2026 John Wiley & Sons Ltd.)
References:	Ahola, S., P. Rivera Mejías, S. Hermans, et al. 2022. “OMA1‐Mediated Integrated Stress Response Protects Against Ferroptosis in Mitochondrial Cardiomyopathy.” Cell Metabolism 34: 1875–1891.e7. https://doi.org/10.1016/j.cmet.2022.08.017. Alvarez, S. W., V. O. Sviderskiy, E. M. Terzi, et al. 2017. “NFS1 Undergoes Positive Selection in Lung Tumours and Protects Cells From Ferroptosis.” Nature 551: 639–643. https://doi.org/10.1038/nature24637. Bai, T., M. Li, Y. Liu, Z. Qiao, and Z. Wang. 2020. “Inhibition of Ferroptosis Alleviates Atherosclerosis Through Attenuating Lipid Peroxidation and Endothelial Dysfunction in Mouse Aortic Endothelial Cell.” Free Radical Biology & Medicine 160: 92–102. https://doi.org/10.1016/j.freeradbiomed.2020.07.026. Bersuker, K., J. M. Hendricks, Z. Li, et al. 2019. “The CoQ Oxidoreductase FSP1 Acts Parallel to GPX4 to Inhibit Ferroptosis.” Nature 575: 688–692. https://doi.org/10.1038/s41586-019-1705-2. Bloom, S. I., M. T. Islam, L. A. Lesniewski, and A. J. Donato. 2023. “Mechanisms and Consequences of Endothelial Cell Senescence.” Nature Reviews. Cardiology 20: 38–51. https://doi.org/10.1038/s41569-022-00739-0. Boos, C. J., G. Y. H. Lip, and A. D. Blann. 2006. “Circulating Endothelial Cells in Cardiovascular Disease.” Journal of the American College of Cardiology 48: 1538–1547. https://doi.org/10.1016/j.jacc.2006.02.078. Chen, J., Z. Ruan, H. Lou, et al. 2022. “First‐In‐Human Study to Investigate the Safety and Pharmacokinetics of Salvianolic Acid A and Pharmacokinetic Simulation Using a Physiologically Based Pharmacokinetic Model.” Frontiers in Pharmacology 13: 907208. https://doi.org/10.3389/fphar.2022.907208. Cornelissen, A., L. Guo, A. Sakamoto, R. Virmani, and A. V. Finn. 2019. “New Insights Into the Role of Iron in Inflammation and Atherosclerosis.” eBioMedicine 47: 598–606. https://doi.org/10.1016/j.ebiom.2019.08.014. Del Re, D. P., D. Amgalan, A. Linkermann, Q. Liu, and R. N. Kitsis. 2019. “Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease.” Physiological Reviews 99: 1765–1817. https://doi.org/10.1152/physrev.00022.2018. Dixon, S. J., and B. R. Stockwell. 2019. “The Hallmarks of Ferroptosis.” Annual Review of Cancer Biology 3: 35–54. https://doi.org/10.1146/annurev-cancerbio-030518-055844. Doll, S., F. P. Freitas, R. Shah, et al. 2019. “FSP1 Is a Glutathione‐Independent Ferroptosis Suppressor.” Nature 575: 693–698. https://doi.org/10.1038/s41586-019-1707-0. Eelen, G., P. de Zeeuw, L. Treps, U. Harjes, B. W. Wong, and P. Carmeliet. 2018. “Endothelial Cell Metabolism.” Physiological Reviews 98: 3–58. https://doi.org/10.1152/physrev.00001.2017. Fang, X., H. Ardehali, J. Min, and F. Wang. 2023. “The Molecular and Metabolic Landscape of Iron and Ferroptosis in Cardiovascular Disease.” Nature Reviews. Cardiology 20: 7–23. https://doi.org/10.1038/s41569-022-00735-4. Gan, B. 2021. “Mitochondrial Regulation of Ferroptosis.” Journal of Cell Biology 220: e202105043. https://doi.org/10.1083/jcb.202105043. Gao, M., J. Yi, J. Zhu, et al. 2019. “Role of Mitochondria in Ferroptosis.” Molecular Cell 73: 354–363.e3. https://doi.org/10.1016/j.molcel.2018.10.042. Godo, S., and H. Shimokawa. 2017. “Endothelial Functions.” Arteriosclerosis, Thrombosis, and Vascular Biology 37: e108‐e114. https://doi.org/10.1161/ATVBAHA.117.309813. Hebbel, R. P. 2017. “Blood Endothelial Cells: Utility From Ambiguity.” Journal of Clinical Investigation 127: 1613–1615. https://doi.org/10.1172/JCI93649. Heinrich, M., G. Appendino, T. Efferth, et al. 2020. “Best Practice in Research—Overcoming Common Challenges in Phytopharmacological Research.” Journal of Ethnopharmacology 246: 112230. https://doi.org/10.1016/j.jep.2019.112230. Hu, Q., W. Wei, D. Wu, et al. 2022. “Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin‐Induced Ferroptosis.” Frontiers in Cell and Development Biology 10: 810327. https://doi.org/10.3389/fcell.2022.810327. Iwabu, M., T. Yamauchi, M. Okada‐Iwabu, et al. 2010. “Adiponectin and AdipoR1 Regulate PGC‐1α and Mitochondria by Ca2+ and AMPK/SIRT1.” Nature 464: 1313–1319. https://doi.org/10.1038/nature08991. Jiang, X., B. R. Stockwell, and M. Conrad. 2021. “Ferroptosis: Mechanisms, Biology and Role in Disease.” Nature Reviews. Molecular Cell Biology 22: 266–282. https://doi.org/10.1038/s41580-020-00324-8. Kakino, A., Y. Fujita, L.‐Y. Ke, et al. 2021. “Adiponectin Forms a Complex With Atherogenic LDL and Inhibits Its Downstream Effects.” Journal of Lipid Research 62: 100001. https://doi.org/10.1194/jlr.RA120000767. Le, Y., H. Shen, Z. Yang, D. Lu, and C. Wang. 2021. “Comprehensive Analysis of Organophosphorus Flame Retardant‐Induced Mitochondrial Abnormalities: Potential Role in Lipid Accumulation.” Environmental Pollution 274: 116541. https://doi.org/10.1016/j.envpol.2021.116541. Le, Y., Z. Zhang, C. Wang, and D. Lu. 2021. “Ferroptotic Cell Death: New Regulatory Mechanisms for Metabolic Diseases.” Endocrine, Metabolic & Immune Disorders Drug Targets 21: 785–800. https://doi.org/10.2174/1871530320666200731175328. Li, C., Y. Zhang, J. Liu, R. Kang, D. J. Klionsky, and D. Tang. 2020. “Mitochondrial DNA Stress Triggers Autophagy‐Dependent Ferroptotic Death.” Autophagy 17: 948–960. https://doi.org/10.1080/15548627.2020.1739447. Li, L., H. Wang, J. Zhang, X. Chen, Z. Zhang, and Q. Li. 2021. “Effect of Endothelial Progenitor Cell‐Derived Extracellular Vesicles on Endothelial Cell Ferroptosis and Atherosclerotic Vascular Endothelial Injury.” Cell Death Discovery 7: 235. https://doi.org/10.1038/s41420-021-00610-0. Li, Z., S. Xu, and P. Liu. 2018. “ Salvia miltiorrhiza Burge (Danshen): A Golden Herbal Medicine in Cardiovascular Therapeutics.” Acta Pharmacologica Sinica 39: 802–824. https://doi.org/10.1038/aps.2017.193. Liu, B., W. Yi, X. Mao, L. Yang, and C. Rao. 2021. “Enoyl Coenzyme A Hydratase 1 Alleviates Nonalcoholic Steatohepatitis in Mice by Suppressing Hepatic Ferroptosis.” American Journal of Physiology, Endocrinology and Metabolism 320: E925–E937. https://doi.org/10.1152/ajpendo.00614.2020. Liu, W., N. Östberg, M. Yalcinkaya, et al. 2022. “Erythroid Lineage Jak2V617F Expression Promotes Atherosclerosis Through Erythrophagocytosis and Macrophage Ferroptosis.” Journal of Clinical Investigation 132: e155724. https://doi.org/10.1172/JCI155724. Maeda, N., T. Funahashi, Y. Matsuzawa, and I. Shimomura. 2020. “Adiponectin, a Unique Adipocyte‐Derived Factor Beyond Hormones.” Atherosclerosis 292: 1–9. https://doi.org/10.1016/j.atherosclerosis.2019.10.021. Mao, C., X. Liu, Y. Zhang, et al. 2021. “DHODH‐Mediated Ferroptosis Defence Is a Targetable Vulnerability in Cancer.” Nature 593: 586–590. https://doi.org/10.1038/s41586-021-03539-7. Nakamura, T., C. Hipp, A. Santos Dias Mourão, et al. 2023. “Phase Separation of FSP1 Promotes Ferroptosis.” Nature 619: 371–377. https://doi.org/10.1038/s41586-023-06255-6. Ng, M. Y. W., T. Wai, and A. Simonsen. 2021. “Quality Control of the Mitochondrion.” Developmental Cell 56: 881–905. https://doi.org/10.1016/j.devcel.2021.02.009. Ni, H.‐M., J. A. Williams, and W.‐X. Ding. 2015. “Mitochondrial Dynamics and Mitochondrial Quality Control.” Redox Biology 4: 6–13. https://doi.org/10.1016/j.redox.2014.11.006. Okada‐Iwabu, M., T. Yamauchi, M. Iwabu, et al. 2013. “A Small‐Molecule AdipoR Agonist for Type 2 Diabetes and Short Life in Obesity.” Nature 503: 493–499. https://doi.org/10.1038/nature12656. Ouyang, S., J. You, C. Zhi, et al. 2021. “Ferroptosis: The Potential Value Target in Atherosclerosis.” Cell Death & Disease 12: 782. https://doi.org/10.1038/s41419-021-04054-3. Palomer, X., J. Pizarro‐Delgado, and M. Vázquez‐Carrera. 2018. “Emerging Actors in Diabetic Cardiomyopathy: Heartbreaker Biomarkers or Therapeutic Targets?” Trends in Pharmacological Sciences 39: 452–467. https://doi.org/10.1016/j.tips.2018.02.010. Pickles, S., P. Vigié, and R. J. Youle. 2018. “Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance.” Current Biology 28: R170–R185. https://doi.org/10.1016/j.cub.2018.01.004. Sharma, A., M. Mah, R. H. Ritchie, and M. J. De Blasio. 2022. “The Adiponectin Signalling Pathway ‐ A Therapeutic Target for the Cardiac Complications of Type 2 Diabetes?” Pharmacology & Therapeutics 232: 108008. https://doi.org/10.1016/j.pharmthera.2021.108008. Shen, K., X. Wang, Y. Wang, et al. 2023. “miR‐125b‐5p in Adipose Derived Stem Cells Exosome Alleviates Pulmonary Microvascular Endothelial Cells Ferroptosis via Keap1/Nrf2/GPX4 in Sepsis Lung Injury.” Redox Biology 62: 102655. https://doi.org/10.1016/j.redox.2023.102655. Shimano, M., N. Ouchi, R. Shibata, et al. 2010. “Adiponectin Deficiency Exacerbates Cardiac Dysfunction Following Pressure Overload Through Disruption of an AMPK‐Dependent Angiogenic Response.” Journal of Molecular and Cellular Cardiology 49: 210–220. https://doi.org/10.1016/j.yjmcc.2010.02.021. Song, N., H. Xu, S. Wu, et al. 2023. “Synergistic Activation of AMPK by AdipoR1/2 Agonist and Inhibitor of EDPs–EBP Interaction Recover NAFLD Through Enhancing Mitochondrial Function in Mice.” Acta Pharmaceutica Sinica B 13: 542–558. https://doi.org/10.1016/j.apsb.2022.10.003. Sopić, M., J. Joksić, V. Spasojević‐Kalimanovska, D. Kalimanovska‐Oštrić, K. Anđelković, and Z. Jelić‐Ivanović. 2015. “Are Decreased AdipoR1 mRNA Levels Associated With Adiponectin Resistance in Coronary Artery Disease Patients?” Clinical and Experimental Pharmacology & Physiology 42: 331–336. https://doi.org/10.1111/1440-1681.12361. Takahashi, Y., R. Watanabe, Y. Sato, et al. 2018. “Novel Phytopeptide Osmotin Mimics Preventive Effects of Adiponectin on Vascular Inflammation and Atherosclerosis.” Metabolism 83: 128–138. https://doi.org/10.1016/j.metabol.2018.01.010. Tanabe, H., Y. Fujii, M. Okada‐Iwabu, et al. 2015. “Crystal Structures of the Human Adiponectin Receptors.” Nature 520: 312–316. https://doi.org/10.1038/nature14301. Trimm, E., and K. Red‐Horse. 2023. “Vascular Endothelial Cell Development and Diversity.” Nature Reviews. Cardiology 20: 197–210. https://doi.org/10.1038/s41569-022-00770-1. Wang, X., Q. Chen, H. Pu, et al. 2016. “Adiponectin Improves NF‐κB‐Mediated Inflammation and Abates Atherosclerosis Progression in Apolipoprotein E‐Deficient Mice.” Lipids in Health and Disease 15: 33. https://doi.org/10.1186/s12944-016-0202-y. Wang, X., A. A. Izzo, A. Papapetropoulos, et al. 2024. “Natural Product Pharmacology: The British Journal of Pharmacology Perspective.” British Journal of Pharmacology 181: 3547–3555. https://doi.org/10.1111/bph.17300. Wang, X., Q. Li, B. Sui, M. Xu, Z. Pu, and T. Qiu. 2022. “Schisandrin A From Schisandra Chinensis Attenuates Ferroptosis and NLRP3 Inflammasome‐Mediated Pyroptosis in Diabetic Nephropathy Through Mitochondrial Damage by AdipoR1 Ubiquitination.” Oxidative Medicine and Cellular Longevity 2022: 1–23. https://doi.org/10.1155/2022/5411462. Wang, X., Y. Shen, M. Shang, X. Liu, and L. L. Munn. 2023. “Endothelial Mechanobiology in Atherosclerosis.” Cardiovascular Research 119: 1656–1675. https://doi.org/10.1093/cvr/cvad076. Xiang, P., Q. Chen, L. Chen, et al. 2023. “Metabolite Neu5Ac Triggers SLC3A2 Degradation Promoting Vascular Endothelial Ferroptosis and Aggravates Atherosclerosis Progression in ApoE ‐/‐ Mice.” Theranostics 13: 4993–5016. https://doi.org/10.7150/thno.87968. Xu, Y., and J. C. Kovacic. 2023. “Endothelial to Mesenchymal Transition in Health and Disease.” Annual Review of Physiology 85: 245–267. https://doi.org/10.1146/annurev-physiol-032222-080806. Yang, M.‐Y., Z.‐Y. Song, H.‐L. Gan, et al. 2022. “Non‐Clinical Safety Evaluation of Salvianolic Acid A: Acute, 4‐Week Intravenous Toxicities and Genotoxicity Evaluations.” BMC Pharmacology and Toxicology 23: 83. https://doi.org/10.1186/s40360-022-00622-1. Yang, W. S., R. SriRamaratnam, M. E. Welsch, et al. 2014. “Regulation of Ferroptotic Cancer Cell Death by GPX4.” Cell 156: 317–331. https://doi.org/10.1016/j.cell.2013.12.010. Zhang, J., J. Tong, D. Sun, J. Fu, D. Li, and P. Wang. 2023. “Targeting Ferroptosis in Cardio‐Metabolic‐Diseases: Mechanisms and Therapeutic Prospects.” Medicinal Research Reviews 43: 683–712. https://doi.org/10.1002/med.21934. Zhang, Z., J. Tang, J. Song, et al. 2022. “Elabela Alleviates Ferroptosis, Myocardial Remodeling, Fibrosis and Heart Dysfunction in Hypertensive Mice by Modulating the IL‐6/STAT3/GPX4 Signaling.” Free Radical Biology & Medicine 181: 130–142. https://doi.org/10.1016/j.freeradbiomed.2022.01.020. Zheng, J., and M. Conrad. 2020. “The Metabolic Underpinnings of Ferroptosis.” Cell Metabolism 32: 920–937. https://doi.org/10.1016/j.cmet.2020.10.011. Zhou, W., W.‐F. Yuan, C. Chen, S.‐M. Wang, and S.‐W. Liang. 2016. “Study on Material Base and Action Mechanism of Compound Danshen Dripping Pills for Treatment of Atherosclerosis Based on Modularity Analysis.” Journal of Ethnopharmacology 193: 36–44. https://doi.org/10.1016/j.jep.2016.07.014. Zhou, Y., H. Zhou, L. Hua, et al. 2021. “Verification of Ferroptosis and Pyroptosis and Identification of PTGS2 as the Hub Gene in Human Coronary Artery Atherosclerosis.” Free Radical Biology & Medicine 171: 55–68. https://doi.org/10.1016/j.freeradbiomed.2021.05.009.
Grant Information:	82574647 National Natural Science Foundation of China; 82074079 National Natural Science Foundation of China; LY24H280001 Natural Science Foundation of Zhejiang Province; LY20H280007 Natural Science Foundation of Zhejiang Province; 2025M784002 China Postdoctoral Science Foundation (CPSF); GZC20252570 Postdoctoral Fellowship Program of China Postdoctoral Science Foundation; 2024RCZXZK49 Research Project of Zhejiang Chinese Medical University
Contributed Indexing:	Keywords: AdipoR1; atherosclerosis; endothelial cells; ferroptosis; mitochondria; salvianolic acid A
Substance Nomenclature:	0 (Caffeic Acids) 51622542XO (salvianolic acid A) 0 (Lactates) 0 (Receptors, Adiponectin) 0 (Reactive Oxygen Species) 0 (ADIPOR1 protein, human) EC 2.7.11.31 (AMP-Activated Protein Kinases)
Entry Date(s):	Date Created: 20260717 Date Completed: 20261005 Latest Revision: 20261005
Update Code:	20261005
DOI:	10.1002/ptr.70419
PMID:	42469155
Βάση Δεδομένων:	MEDLINE

καταχωρήστε σχόλιο πρώτοι!