{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:43:50Z","timestamp":1785930230020,"version":"3.56.0"},"reference-count":55,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease defined by persistent synovial inflammation, progressive cartilage and bone erosion, and extra-articular manifestations. Current treatments, such as disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, and non-steroidal anti-inflammatory drugs (NSAIDs), control disease activity but are limited by toxicity, reduced response over time, and are expensive, demonstrating the need for safer and more effective adjuncts. The marine environment is a rich, largely untapped source of structurally diverse bioactive molecules that could be used to develop new therapeutics. This review compiles current evidence on anti-inflammatory and immunomodulatory compounds from marine organisms relevant to RA, including macroalgae, true marine microalgae, marine microorganisms (bacteria and fungi, including deep-sea taxa), sea cucumbers, sponges, mussels, corals, and jellyfish. Recurring mechanisms of action include inhibition of the NF-\u03baB, MAPK, and JAK\/STAT signalling cascades; suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); reduced production of tumour necrosis factor-\u03b1 (TNF-\u03b1), interleukin (IL)-1\u03b2, and IL-6; and activation of the Nrf2 antioxidant response. Particular attention is given to functional lipids (eicosapentaenoic and docosahexaenoic acids, prostaglandin-like oxylipins) and pigments (astaxanthin, fucoxanthin, \u03b2-carotene) from marine microalgae and heterotrophic protists, which recent literature identifies as the most clinically advanced marine leads. To clarify translational status, compounds are grouped by their development stage (marketed nutraceutical, clinical trial, or preclinical) and summarised in a dedicated table. Some compounds, such as green-lipped mussel extract, microalgal omega-3 oils, and astaxanthin, have reached the stage of randomised controlled trials for arthritis. However, most other potential treatments are still in the early, preclinical phase. It is worth noting that ocean-derived compounds appear generally safe, but more thorough studies, especially in living organisms and in clinical settings, are needed to confirm their effectiveness for rheumatoid arthritis before any claims can be made about their therapeutic benefits.<\/jats:p>","DOI":"10.3390\/nu18152558","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T10:41:42Z","timestamp":1785926502000},"page":"2558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Potentials of Marine-Derived Compounds in Rheumatoid Arthritis"],"prefix":"10.3390","volume":"18","author":[{"given":"Rowena","family":"Thekkekara","sequence":"first","affiliation":[{"name":"College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupama Bangra","family":"Kulur","sequence":"additional","affiliation":[{"name":"College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Seymour","sequence":"additional","affiliation":[{"name":"Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Cairns, QLD 4870, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haleagrahara","family":"Nagaraja","sequence":"additional","affiliation":[{"name":"College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S18","DOI":"10.1016\/S0720-048X(98)00038-2","article-title":"The clinical features of rheumatoid arthritis","volume":"27","author":"Grassi","year":"1998","journal-title":"Eur. J. Radiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e509","DOI":"10.1002\/mco2.509","article-title":"Rheumatoid arthritis: Pathogenesis and therapeutic advances","volume":"5","author":"Gao","year":"2024","journal-title":"MedComm"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S0140-6736(01)06075-5","article-title":"Rheumatoid arthritis","volume":"358","author":"Lee","year":"2001","journal-title":"Lancet"},{"key":"ref_4","unstructured":"Chauhan, K., Jandu, J.S., Brent, L.H., and Al-Dhahir, M.A. (2023). Rheumatoid Arthritis, StatPearls Publishing."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1016\/S0140-6736(17)31491-5","article-title":"Novel treatment strategies in rheumatoid arthritis","volume":"389","author":"Burmester","year":"2017","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1039\/D3NP00061C","article-title":"Marine natural products","volume":"41","author":"Carroll","year":"2024","journal-title":"Nat. Prod. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.berh.2017.08.003","article-title":"Genetic and environmental risk factors for rheumatoid arthritis","volume":"31","author":"Deane","year":"2017","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/s41392-023-01331-9","article-title":"Signaling pathways in rheumatoid arthritis: Implications for targeted therapy","volume":"8","author":"Ding","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/s41584-020-0413-5","article-title":"Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes","volume":"16","author":"Nygaard","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lin, Y.-J., Anzaghe, M., and Schulke, S. (2020). Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells, 9.","DOI":"10.3390\/cells9040880"},{"key":"ref_12","first-page":"667","article-title":"Mechanism of action of methotrexate: Experimental evidence that methotrexate blocks the binding of interleukin 1-beta to the interleukin 1 receptor on target cells","volume":"31","author":"Brody","year":"1993","journal-title":"Eur. J. Clin. Chem. Clin. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1001\/jama.2018.13103","article-title":"Diagnosis and management of rheumatoid arthritis: A review","volume":"320","author":"Aletaha","year":"2018","journal-title":"JAMA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1136\/annrheumdis-2013-203440","article-title":"Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: A double-blind, randomised, controlled trial in new-onset, treatment-naive rheumatoid arthritis (the IDEA study)","volume":"73","author":"Nam","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_15","first-page":"16","article-title":"Methotrexate in rheumatoid arthritis: A quarter century of development","volume":"124","author":"Weinblatt","year":"2013","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.pop.2018.02.010","article-title":"Early diagnosis and treatment of rheumatoid arthritis","volume":"45","author":"Littlejohn","year":"2018","journal-title":"Prim. Care"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1136\/annrheumdis-2015-209057","article-title":"Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naive patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study","volume":"76","author":"Emery","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1002\/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7","article-title":"Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: A forty-eight week, multicenter, randomized, double-blind, placebo-controlled study","volume":"44","author":"Laan","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1001\/jama.295.19.2275","article-title":"Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: A systematic review and meta-analysis","volume":"295","author":"Bongartz","year":"2006","journal-title":"JAMA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1002\/1529-0131(200112)44:12<2862::AID-ART474>3.0.CO;2-W","article-title":"Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides","volume":"44","author":"Mohan","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/BOR.0000000000000153","article-title":"Combination conventional DMARDs compared to biologicals: What is the evidence?","volume":"27","author":"Sethi","year":"2015","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_22","first-page":"1","article-title":"Low-dose prednisone therapy for patients with early active rheumatoid arthritis: Clinical efficacy, disease-modifying properties, and side effects: A randomized, double-blind, placebo-controlled clinical trial","volume":"136","author":"Jacobs","year":"2002","journal-title":"Ann. Intern. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1001\/jama.284.10.1247","article-title":"Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial","volume":"284","author":"Silverstein","year":"2000","journal-title":"JAMA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2147\/JPR.S75160","article-title":"New insights into the use of currently available non-steroidal anti-inflammatory drugs","volume":"8","author":"Brune","year":"2015","journal-title":"J. Pain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/ar4174","article-title":"Use of NSAIDs in treating patients with arthritis","volume":"15","author":"Crofford","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yang, G., Lin, M., Kaliaperumal, K., Lu, Y., Qi, X., Jiang, X., Xu, X., Gao, C., Liu, Y., and Luo, X. (2024). Recent advances in anti-inflammatory compounds from marine microorganisms. Mar. Drugs, 22.","DOI":"10.3390\/md22090424"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/j.intimp.2011.04.003","article-title":"Antioxidant and anti-inflammatory effect of polysaccharides from Lobophora variegata on zymosan-induced arthritis in rats","volume":"11","author":"Paiva","year":"2011","journal-title":"Int. Immunopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Costa, V.V., Amaral, F.A., Coelho, F.M., Queiroz-Junior, C.M., Malagoli, B.G., Gomes, J.H.S., Lopes, F., Silveira, K.D., Sachs, D., and Fagundes, C.T. (2015). Lithothamnion muelleri treatment ameliorates inflammatory and hypernociceptive responses in antigen-induced arthritis in mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118356"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cutolo, E.A., Caferri, R., Campitiello, R., and Cutolo, M. (2023). The clinical promise of microalgae in rheumatoid arthritis: From natural compounds to recombinant therapeutics. Mar. Drugs, 21.","DOI":"10.3390\/md21120630"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"118","DOI":"10.4103\/0974-8490.172660","article-title":"Inhibition of pro-inflammatory mediators and cytokines by Chlorella vulgaris extracts","volume":"8","author":"Sibi","year":"2016","journal-title":"Pharmacogn. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"111","DOI":"10.4490\/algae.2013.28.1.111","article-title":"In vitro studies of anti-inflammatory and anticancer activities of organic solvent extracts from cultured marine microalgae","volume":"28","author":"Samarakoon","year":"2013","journal-title":"Algae"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s10811-012-9869-2","article-title":"Mono- and digalactosyldiacylglycerols: Potent nitric oxide inhibitors from the marine microalga Nannochloropsis granulata","volume":"25","author":"Banskota","year":"2013","journal-title":"J. Appl. Phycol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5402","DOI":"10.3390\/md13085402","article-title":"The anti-inflammatory effect of algae-derived lipid extracts on lipopolysaccharide (LPS)-stimulated human THP-1 macrophages","volume":"13","author":"Robertson","year":"2015","journal-title":"Mar. Drugs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.clnu.2017.02.021","article-title":"Docosahexaenoic acid in the treatment of rheumatoid arthritis: A double-blind, placebo-controlled, randomized cross-over study with microalgae vs. sunflower oil","volume":"37","author":"Dawczynski","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5850","DOI":"10.1039\/D5FO00949A","article-title":"Astaxanthin supplement improves clinical outcomes, quality of life, and inflammatory factors in patients with rheumatoid arthritis: A randomized clinical trial","volume":"16","author":"Grigorian","year":"2025","journal-title":"Food Funct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ejphar.2010.09.032","article-title":"Fucoxanthin inhibits the inflammatory response by suppressing the activation of NF-\u03baB and MAPKs in lipopolysaccharide-induced RAW 264.7 macrophages","volume":"649","author":"Kim","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Li, W., Tang, X.-X., Yan, X., Wu, Z., Yi, Z.-W., Fang, M.-J., Su, X., and Qiu, Y.-K. (2016). Macrolactins from marine-derived Bacillus subtilis B5 bacteria as inhibitors of inducible nitric oxide and cytokines expression. Mar. Drugs, 14.","DOI":"10.3390\/md14110195"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4510","DOI":"10.3390\/md11114510","article-title":"Penicillinolide A: A new anti-inflammatory metabolite from the marine fungus Penicillium sp. SF-5292","volume":"11","author":"Lee","year":"2013","journal-title":"Mar. Drugs"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.phanu.2018.03.002","article-title":"Sea cucumber (Isostichopus badionotus) body-wall preparations exert anti-inflammatory activity in vivo","volume":"6","author":"Grant","year":"2018","journal-title":"PharmaNutrition"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.bmc.2011.10.086","article-title":"Marine sponge Hymeniacidon sp. amphilectane metabolites potently inhibit rat brain microglia thromboxane B2 generation","volume":"20","author":"Mayer","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1080\/13880209.2017.1373832","article-title":"Lipophilic fractions from the marine sponge Halichondria sitiens decrease secretion of pro-inflammatory cytokines by dendritic cells and decrease their ability to induce a Th1 type response by allogeneic CD4+ T cells","volume":"55","author":"Di","year":"2017","journal-title":"Pharm. Biol."},{"key":"ref_42","unstructured":"Jacobs, R.S., and Faulkner, D.J. (1984). Manoalide, an Anti-Inflammatory Analgesic Marine Natural Product. (4,447,445), U.S. Patent."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"625","DOI":"10.3390\/nu7010625","article-title":"Lipid extract from hard-shelled mussel (Mytilus coruscus) improves clinical conditions of patients with rheumatoid arthritis: A randomized controlled trial","volume":"7","author":"Fu","year":"2015","journal-title":"Nutrients"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"568","DOI":"10.3390\/md12020568","article-title":"Anti-inflammatory activity and mechanism of a lipid extract from hard-shelled mussel (Mytilus coruscus) on chronic arthritis in rats","volume":"12","author":"Li","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/S0965-2299(98)80003-4","article-title":"The treatment of arthritis with a lipid extract of Perna canaliculus: A randomized trial","volume":"6","author":"Gibson","year":"1998","journal-title":"Complement. Ther. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.foodchem.2013.07.027","article-title":"Bioactive compounds from marine mussels and their effects on human health","volume":"142","author":"Grienke","year":"2014","journal-title":"Food Chem."},{"key":"ref_47","first-page":"212","article-title":"Clinical efficacy and safety of Lyprinol, a patented extract from New Zealand green-lipped mussel (Perna canaliculus), in patients with osteoarthritis of the hip and knee: A multicenter 2-month clinical trial","volume":"35","author":"Cho","year":"2003","journal-title":"Allerg. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.3390\/md13052559","article-title":"Anti-inflammatory and analgesic effects of the marine-derived compound excavatolide B isolated from the culture-type Formosan gorgonian Briareum excavatum","volume":"13","author":"Lin","year":"2015","journal-title":"Mar. Drugs"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"472","DOI":"10.3390\/md7030472","article-title":"Excavatoids E and F: Discovery of two new briaranes from the cultured octocoral Briareum excavatum","volume":"7","author":"Sung","year":"2009","journal-title":"Mar. Drugs"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Lin, Y.-Y., Jean, Y.-H., Lee, H.-P., Chen, W.-F., Sun, Y.-M., Su, J.-H., Lu, Y., Huang, S.-Y., Hung, H.-C., and Sung, P.-J. (2013). A soft coral-derived compound, 11-epi-sinulariolide acetate, suppresses inflammatory response and bone destruction in adjuvant-induced arthritis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062926"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"184959","DOI":"10.1155\/2014\/184959","article-title":"Corals and their potential applications to integrative medicine","volume":"2014","author":"Cooper","year":"2014","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Teng, L., Wang, X., Yu, H., Li, R., Geng, H., Xing, R., Liu, S., and Li, P. (2023). Jellyfish peptide as an alternative source of antioxidant. Antioxidants, 12.","DOI":"10.3390\/antiox12030742"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1080\/21691401.2018.1480490","article-title":"Upcycling of jellyfish (Nemopilema nomurai) sea wastes as highly valuable reducing agents for green synthesis of gold nanoparticles and their antitumor and anti-inflammatory activity","volume":"46","author":"Ahn","year":"2018","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ijbiomac.2021.02.074","article-title":"Jellyfish venom proteins and their pharmacological potentials: A review","volume":"176","author":"Nisa","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1016\/j.biopha.2016.11.010","article-title":"Evaluation of anti-proliferative and anti-inflammatory activities of Pelagia noctiluca venom in lipopolysaccharide\/interferon-gamma stimulated RAW 264.7 macrophages","volume":"84","author":"Ayed","year":"2016","journal-title":"Biomed. Pharmacother."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/15\/2558\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T10:46:42Z","timestamp":1785926802000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/15\/2558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":55,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["nu18152558"],"URL":"https:\/\/doi.org\/10.3390\/nu18152558","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]}}}