Multi-mechanistic cardiovascular potential of sea cucumber compounds: A narrative review of preclinical evidence
DOI:
https://doi.org/10.35335/midwifery.v14i4.2480Keywords:
Anticoagulant, Atherosclerosis, Fucosylated Chondroitin Sulfate, Holothuroidea, HypertensionAbstract
Background: Cardiovascular disease is the leading cause of death worldwide, and residual risk persists despite current drugs. Objectives: To compare the strength of preclinical evidence for sea cucumber (Holothuroidea) compounds across four cardiovascular mechanisms and identify studies needed before clinical testing. Methods: This SANRA-guided narrative review included peer-reviewed English-language studies of sea cucumber-derived compounds with cardiovascular-relevant endpoints. After a five-database search (January 2020–April 2026), PubMed was searched on 29 September 2026 (January 2020–June 2026); 37 of 187 records and 13 articles from other sources were included. Primary studies were graded on five evidence levels, and in vivo studies were assessed with SYRCLE's tool. Results: The evidence base comprised 36 primary studies, none clinical, and 14 reviews. Eight had in vivo cardiovascular endpoints, eight in vivo indirect endpoints, 17 in vitro, ex vivo, or structural endpoints, and three in silico only. Risk of bias was unclear in most domains. Of the four mechanisms, anticoagulant activity had the strongest evidence: fucosylated chondroitin sulfate selectively inhibited the intrinsic tenase complex, prevented thrombosis in rodents with less bleeding than heparin, and remained active orally in two rat studies. An intravenous angiotensin-converting enzyme inhibitory peptide lowered blood pressure in rats with hypertension. Phospholipids and an ultrafine powder reduced aortic plaque in mice with atherosclerosis. Anti-inflammatory effects came mainly from non-vascular models. Conclusions: Sea cucumber compounds have multi-mechanistic cardiovascular potential, but the evidence is preclinical, pharmacokinetic data are limited, and no controlled clinical trial was identified. Pharmacokinetic, toxicity, and oral efficacy studies must precede randomised trials.
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Baethge, C., Goldbeck-Wood, S., & Mertens, S. (2019). SANRA—a scale for the quality assessment of narrative review articles. Research Integrity and Peer Review, 4, 5. https://doi.org/10.1186/s41073-019-0064-8
Debi, P. R., Barua, H., Ahmmed, M. K., & Bhowmik, S. (2025). Therapeutic potential of sea cucumber-derived bioactives in the prevention and management of brain-related disorders: A comprehensive review. Marine Drugs, 23(8), 310. https://doi.org/10.3390/md23080310
Dwivedi, R., Maurya, A. K., Ahmed, H., Farrag, M., & Pomin, V. H. (2024). Nuclear magnetic resonance-based structural elucidation of novel marine glycans and derived oligosaccharides. Magnetic Resonance in Chemistry, 62(4), 269–285. https://doi.org/10.1002/mrc.5377
Dwivedi, R., & Pomin, V. H. (2020). Marine antithrombotics. Marine Drugs, 18(10), 514. https://doi.org/10.3390/md18100514
Dwivedi, R., Sharma, P., Eilts, F., Zhang, F., Linhardt, R. J., Tandon, R., & Pomin, V. H. (2023). Anti-SARS-CoV-2 and anticoagulant properties of Pentacta pygmaea fucosylated chondroitin sulfate depend on high molecular weight structures. Glycobiology, 33(1), 75–85. https://doi.org/10.1093/glycob/cwac063
Fagbohun, O. F., Joseph, J. S., Oriyomi, O. V, & Rupasinghe, H. P. V. (2023). Saponins of North Atlantic sea cucumber: Chemistry, health benefits, and future prospectives. Marine Drugs, 21(5), 262. https://doi.org/10.3390/md21050262
Farrag, M., Dwivedi, R., Sharma, P., Kumar, D., Tandon, R., & Pomin, V. H. (2023). Structural requirements of Holothuria floridana fucosylated chondroitin sulfate oligosaccharides in anti-SARS-CoV-2 and anticoagulant activities. PLOS ONE, 18(5), e0285539. https://doi.org/10.1371/journal.pone.0285539
Felix, A. L., Penno, S. M., Bezerra, F. F., & Mourão, P. A. S. (2025). Fucosylated chondroitin sulfate, an intriguing polysaccharide from sea cucumber: Past, present, and future. Glycobiology, 35(2), cwae098. https://doi.org/10.1093/glycob/cwae098
Festa, M., Sansone, C., Brunet, C., Crocetta, F., Di Paola, L., Lombardo, M., Bruno, A., Noonan, D. M., & Albini, A. (2020). Cardiovascular active peptides of marine origin with ACE inhibitory activities: Potential role as anti-hypertensive drugs and in prevention of SARS-CoV-2 infection. International Journal of Molecular Sciences, 21(21), 8364. https://doi.org/10.3390/ijms21218364
Gao, N., Chen, R., Mou, R., Xiang, J., Zhou, K., Li, Z., & Zhao, J. (2020). Purification, structural characterization and anticoagulant activities of four sulfated polysaccharides from sea cucumber Holothuria fuscopunctata. International Journal of Biological Macromolecules, 164, 3421–3428. https://doi.org/10.1016/j.ijbiomac.2020.08.150
Ghelani, H., Hanspal, K., Talo, L., Talo, S., Altaher, H., Sarsour, H., Tabbal, M., Badawi, S., Collin, P., Adrian, T. E., & Jan, R. K. (2025). Anti-inflammatory effects of Frondanol, a nutraceutical extract from Cucumaria frondosa, via modulation of NF-κB and MAPK pathways in LPS-induced RAW 264.7 cells. Frontiers in Pharmacology, 16, 1683630. https://doi.org/10.3389/fphar.2025.1683630
Ghelani, H., Khursheed, M., Adrian, T. E., & Jan, R. K. (2022). Anti-inflammatory effects of compounds from echinoderms. Marine Drugs, 20(11), 693. https://doi.org/10.3390/md20110693
Hong, Y., Pan, Y., Zhu, G., Wen, J., Chen, R., Cui, L., Chen, H., Wu, T., Yin, R., & Zhao, J. (2026). Structure characterization and multi-target inhibitory activities of fucosylated chondroitin sulfate from sea cucumber Thelenota anax. Carbohydrate Polymers, 388, 125591. https://doi.org/10.1016/j.carbpol.2026.125591
Hooijmans, C. R., Rovers, M. M., de Vries, R. B. M., Leenaars, M., Ritskes-Hoitinga, M., & Langendam, M. W. (2014). SYRCLE’s risk of bias tool for animal studies. BMC Medical Research Methodology, 14, 43. https://doi.org/10.1186/1471-2288-14-43
Hossain, A., Dave, D., & Shahidi, F. (2020). Northern sea cucumber (Cucumaria frondosa): A potential candidate for functional food, nutraceutical, and pharmaceutical sector. Marine Drugs, 18(5), 274. https://doi.org/10.3390/md18050274
Hossain, A., Dave, D., & Shahidi, F. (2023). Sulfated polysaccharides in sea cucumbers and their biological properties: A review. International Journal of Biological Macromolecules, 253, 127329. https://doi.org/10.1016/j.ijbiomac.2023.127329
Hou, T., Liu, X., Zhang, S., Tang, K., Liu, S., Liu, J., Fan, X., & Wang, Z. (2025). Anti-inflammatory effects of the fucoidan from sea cucumber Apostichopus japonicus. Marine Biotechnology, 27(1), 32. https://doi.org/10.1007/s10126-025-10410-7
Jiang, S., Yin, H., Li, R., Shi, W., Mou, J., & Yang, J. (2021). The activation effects of fucoidan from sea cucumber Stichopus chloronotus on RAW264.7 cells via TLR2/4-NF-κB pathway and its structure-activity relationship. Carbohydrate Polymers, 270, 118353. https://doi.org/10.1016/j.carbpol.2021.118353
La Paglia, L., Vazzana, M., Mauro, M., Dumas, F., Urso, A., Simon, S., Drahos, L., & Vizzini, A. (2026). Identification of antioxidant and anti-inflammatory activity of sea cucumber (Holothuria tubulosa) active peptides by a combined approach of omics data and bioinformatics analysis. Marine Drugs, 24(5), 158. https://doi.org/10.3390/md24050158
Lee, H.-G., Nagahawatta, D. P., Je, J.-G., Oh, J.-Y., Jayawardhana, H. H. A. C. K., Liyanage, N. M., Kurera, M. J. M. S., Park, S.-H., Jeon, Y.-J., Jung, W.-K., Choe, Y. R., & Kim, H.-S. (2024). Identification of structure-linked activity on bioactive peptides from sea cucumber (Stichopus japonicus): A compressive in silico/in vitro study. Frontiers in Bioscience-Landmark, 29(10), 368. https://doi.org/10.31083/j.fbl2910368
Li, H., Yuan, Q., Lv, K., Ma, H., Gao, C., Liu, Y., Zhang, S., & Zhao, L. (2021). Low-molecular-weight fucosylated glycosaminoglycan and its oligosaccharides from sea cucumber as novel anticoagulants: A review. Carbohydrate Polymers, 251, 117034. https://doi.org/10.1016/j.carbpol.2020.117034
Li, S., Li, M., Guo, R., Zhao, T., Gao, X., Li, K., Guo, X., Li, J., & Li, D. (2022). Fucoidans from Pearsonothuria graeffei prevent obesity by regulating intestinal lipid metabolism and inflammation related signalling pathways. Food & Function, 13(23), 12234–12245. https://doi.org/10.1039/d2fo02588d
Li, X., Li, S., Liu, J., Lin, L., Sun, H., Yang, W., Cai, Y., Gao, N., Zhou, L., Qin, H., Yin, R., & Zhao, J. (2021). A regular fucan sulfate from Stichopus herrmanni and its peroxide depolymerization: Structure and anticoagulant activity. Carbohydrate Polymers, 256, 117513. https://doi.org/10.1016/j.carbpol.2020.117513
Liang, Q., Zhong, Y., Ren, X., Liang, Z., Zhu, C., Wang, L., & Mou, H. (2025). Mining for novel umami peptides from sea cucumber viscera hydrolysate with ACE inhibitory activity. Journal of Agricultural and Food Chemistry, 73(25), 15751–15766. https://doi.org/10.1021/acs.jafc.5c04439
Liang, Q., Zhou, W., Peng, S., Liang, Z., Liu, Z., Wang, L., Mukhtar, H., & Mou, H. (2025). Exploration of ACE inhibitory peptides from sea cucumber viscera with DPP-IV inhibitory activity: Virtual screening, characterization, and potential mechanism investigation. International Journal of Biological Macromolecules, 311, 143843. https://doi.org/10.1016/j.ijbiomac.2025.143843
Lin, P., Shen, N., Yin, F., & Guo, S. D. (2022). Sea cucumber-derived compounds for treatment of dyslipidemia: A review. Frontiers in Pharmacology, 13, 1000315. https://doi.org/10.3389/fphar.2022.1000315
Liu, Y., Li, R., Song, L., Li, K., Yu, H., Xing, R., Liu, S., & Li, P. (2024). Intermediate molecular weight-fucosylated chondroitin sulfate from sea cucumber Cucumaria frondosa is a promising anticoagulant targeting intrinsic factor IXa. International Journal of Biological Macromolecules, 269, 131952. https://doi.org/10.1016/j.ijbiomac.2024.131952
Lu, C., Wang, X., Ma, J., Wang, M., Liu, W., Wang, G., Ding, Y., Lin, Z., & Li, Y. (2024). Chemical substances and their activities in sea cucumber Apostichopus japonicus: A review. Archiv Der Pharmazie, 357(1), e2300427. https://doi.org/10.1002/ardp.202300427
Lu, Z., Sun, N., Dong, L., Gao, Y., & Lin, S. (2022). Production of bioactive peptides from sea cucumber and its potential health benefits: A comprehensive review. Journal of Agricultural and Food Chemistry, 70(25), 7607–7625. https://doi.org/10.1021/acs.jafc.2c02696
Mecheta, A., Hanachi, A., Jeandel, C., Arab-Tehrany, E., Bianchi, A., Velot, E., Mezali, K., & Linder, M. (2020). Physicochemical properties and liposomal formulations of hydrolysate fractions of four sea cucumbers (Holothuroidea: Echinodermata) from the northwestern Algerian coast. Molecules, 25(13), 2972. https://doi.org/10.3390/molecules25132972
Nurhidayati, N., Prabowowati, Y. Y., Nurdiana, N., Permatasari, H. K., Rosyidi, R. M., & Endharti, A. T. G. (2025). Bioactive compounds and biological mechanism of sea cucumber as potential antitumor agents: A review. Journal of Pharmacy & Pharmacognosy Research, 13(5), 1372–1384. https://doi.org/10.56499/jppres24.2119_13.5.1372
Ray, K. K., Molemans, B., Schoonen, W. M., Giovas, P., Bray, S., Kiru, G., Murphy, J., Banach, M., De Servi, S., Gaita, D., Gouni-Berthold, I., Hovingh, G. K., Jozwiak, J. J., Jukema, J. W., Kiss, R. G., Kownator, S., Iversen, H. K., Maher, V., Masana, L., … Poulter, N. R. (2021). EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study. European Journal of Preventive Cardiology, 28(11), 1279–1289. https://doi.org/10.1093/eurjpc/zwaa047
Saeid, A., Dave, D., & Shahidi, F. (2025). Polysaccharides from echinoderms: Unlocking health benefits and food applications - a review. Food & Function, 16(14), 5679–5704. https://doi.org/10.1039/d5fo02177d
Sales, S., Lourenço, H. M., Bandarra, N. M., Afonso, C., Matos, J., Botelho, M. J., Pessoa, M. F., Félix, P. M., Veronez, A., & Cardoso, C. (2024). How biological activity in sea cucumbers changes as a function of species and tissue. Foods, 13(1), 35. https://doi.org/10.3390/foods13010035
Sang, X., Xing, Z., Zhou, B., Wang, Y., Guan, X., Wang, F., Li, Y., Zhao, Q., & Li, Z. (2025). Sea cucumber polysaccharides promote gut-liver axis health by modulating microbiota, metabolism, and gene expression in mice. Foods, 14(17), 2962. https://doi.org/10.3390/foods14172962
Senadheera, T. R. L., Hossain, A., Dave, D., & Shahidi, F. (2022). In silico analysis of bioactive peptides produced from underutilized sea cucumber by-products—A bioinformatics approach. Marine Drugs, 20(10), 610. https://doi.org/10.3390/md20100610
Sun, H., Zhu, G., Li, S., Li, P., Zhang, J., Yin, R., Yuan, L., Gao, N., & Zhao, J. (2025). Fucosylated glycosaminoglycan oligosaccharide HS14, derived from sea cucumbers, is a novel inhibitor of platelet Toll-like receptor 2. Marine Drugs, 23(3), 110. https://doi.org/10.3390/md23030110
Sun, J., Sha, L., Zhu, G., Li, L., Li, P., Chen, M., Wang, J., Jiao, X., Gao, N., & Zhao, J. (2026). Persulfate-driven free radical depolymerization of fucosylated chondroitin sulfate and intrinsic Xase inhibition of the resulting oligosaccharides. Carbohydrate Research, 563, 109844. https://doi.org/10.1016/j.carres.2026.109844
Wang, H., He, D., Duan, L., Lv, L., Gao, Q., Wang, Y., Yang, S., & Lv, Z. (2022). In vivo anticoagulant and antithrombic activity of depolymerized glycosaminoglycan from Apostichopus japonicus and dynamic effect-exposure relationship in rat plasma. Marine Drugs, 20(10), 631. https://doi.org/10.3390/md20100631
Wang, Y., Chen, S., Shi, W., Liu, S., Chen, X., Pan, N., Wang, X., Su, Y., & Liu, Z. (2024). Targeted affinity purification and mechanism of action of angiotensin-converting enzyme (ACE) inhibitory peptides from sea cucumber gonads. Marine Drugs, 22(2), 90. https://doi.org/10.3390/md22020090
Wang, Z., Cai, H., Yuan, M., Jiao, J., Song, S., Yu, C., & Dong, X. (2025). Enhancing polysaccharide release rate from sea cucumber powder by ultrafine milling: Improving ability to interfere with atherosclerosis. International Journal of Biological Macromolecules, 327, 146992. https://doi.org/10.1016/j.ijbiomac.2025.146992
Wang, Z., Wang, X., Liu, Y., Wang, X., Meng, N., Cong, P., Song, Y., Xu, J., & Xue, C. (2024). Sea cucumber plasmalogen regulates the lipid profile in high-fat diet mouse liver via lipophagy. Journal of Agricultural and Food Chemistry, 72(17), 9842–9855. https://doi.org/10.1021/acs.jafc.4c00152
Wargasetia, T. L., Ratnawati, H., Widodo, N., & Widyananda, M. H. (2023). Antioxidant and anti-inflammatory activity of sea cucumber (Holothuria scabra) active compounds against KEAP1 and iNOS protein. Bioinformatics and Biology Insights, 17, 11779322221149612. https://doi.org/10.1177/11779322221149613
Wen, L., Li, R., Zhao, Y.-C., Yang, J.-Y., Li, X.-Y., Xue, C.-H., Zhang, T.-T., & Wang, Y.-M. (2022). A comparative study of the anti-obesity effects of dietary sea cucumber saponins and energy restriction in response to weight loss and weight regain in mice. Marine Drugs, 20(10), 629. https://doi.org/10.3390/md20100629
World Health Organization. (2025). Cardiovascular diseases (CVDs). World Health Organization. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
Xu, D., Gong, X., Lin, L., Dong, H., Wen, Y., Li, Y., Fu, G., Ma, Y., Xiong, W., Guan, T., Sun, A., Meng, X., Dong, X., Li, Z., Wu, M., & Li, Z. (2026). Design and synthesis of novel fucosylated chondroitin sulfate derivatives as intrinsic FXase inhibitors and evaluation of their antithrombotic activities. Carbohydrate Polymers, 377, 124839. https://doi.org/10.1016/j.carbpol.2025.124839
Yan, L., Wang, D., Yu, Y., Zhang, F., Ye, X., Linhardt, R. J., & Chen, S. (2020). Fucosylated chondroitin sulfate 9-18 oligomers exhibit molecular size-independent antithrombotic activity while circulating in the blood. ACS Chemical Biology, 15(8), 2232–2246. https://doi.org/10.1021/acschembio.0c00439
Yan, L., Zhu, M., Wang, D., Tao, W., Liu, D., Zhang, F., Linhardt, R. J., Ye, X., & Chen, S. (2021). Oral administration of fucosylated chondroitin sulfate oligomers in gastro-resistant microcapsules exhibits a safe antithrombotic activity. Thrombosis and Haemostasis, 121(1), 15–26. https://doi.org/10.1055/s-0040-1714738
Yang, S., Wang, X., Li, H., Wang, X., Song, Y., Cong, P., Xu, J., & Xue, C. (2023). Sea cucumber phospholipids regulate cholesterol metabolism in high-fat diet-induced ApoE−/− mice. The Journal of Nutrition, 153(6), 1762–1770. https://doi.org/10.1016/j.tjnut.2023.04.017
Yin, H., Li, R., Liu, J., Sun, Y., Zhao, L., Mou, J., & Yang, J. (2024). Fucosylated chondroitin sulfate from sea cucumber Stichopus chloronotus alleviate the intestinal barrier injury and oxidative stress damage in vitro and in vivo. Carbohydrate Polymers, 328, 121722. https://doi.org/10.1016/j.carbpol.2023.121722
Yin, R., Pan, Y., Cai, Y., Yang, F., Gao, N., Ruzemaimaiti, D., & Zhao, J. (2022). Re-understanding of structure and anticoagulation: Fucosylated chondroitin sulfate from sea cucumber Ludwigothurea grisea. Carbohydrate Polymers, 294, 119826. https://doi.org/10.1016/j.carbpol.2022.119826
Zeng, B.-B., Zhang, L.-Y., Chen, C., Zhang, T.-T., Xue, C.-H., Yanagita, T., Li, Z.-J., & Wang, Y.-M. (2020). Sea cucumber sterol alleviates the lipid accumulation in high-fat–fructose diet fed mice. Journal of Agricultural and Food Chemistry, 68(36), 9707–9717. https://doi.org/10.1021/acs.jafc.0c03794
Zhu, Q., Zhuo, H., Yang, L., Ouyang, H., Chen, J., Liu, B., & Huang, H. (2022). A peptide HEPFYGNEGALR from Apostichopus japonicus alleviates acute alcoholic liver injury by enhancing antioxidant response in male C57BL/6J mice. Molecules, 27(18), 5839. https://doi.org/10.3390/molecules27185839
Zhuo, H., Li, G., Li, X., Yu, Y., Su, J., Chen, J., Liang, M., & Huang, H. (2025). Antidepressant effect of the peptide EIILEAGK from Apostichopus japonicus via inflammatory and mitochondrial regulations in a lipopolysaccharide mouse model. Free Radical Biology and Medicine, 240, 197–210. https://doi.org/10.1016/j.freeradbiomed.2025.08.031
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