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This study explored the combined therapeutic effects of metformin and pravastatin on knee OA induced by monosodium iodoacetate (MIA) in rats. The study encompassed five animal groups (<jats:italic>n<\/jats:italic>\u2009=\u200910 per group) which were allocated as follows: group 1 received 100 \u00b5L of sterile saline injected intra-articularly into the left knee joint (control group) while groups 2\u20135 were injected with 2\u00a0mg MIA in 100\u00b5L normal saline into the intraarticular space. After 2\u00a0weeks, group 3 received oral metformin (100\u00a0mg\/kg) for 2\u00a0weeks, group 4 received oral pravastatin (10\u00a0mg\/kg) for 2\u00a0weeks and group 5 received both metformin 100\u00a0mg\/kg and pravastatin 10\u00a0mg\/kg orally for 2\u00a0weeks. The combination of metformin and pravastatin showed to be the most effective in terms of improving radiologic and histologic findings in knee OA. This combination also reduced both serum C reactive protein (CRP) and cartilage oligomeric matrix protein (COMP), while increasing serum collagen type II (COL2). Combining metformin and pravastatin also reduced AKT1, PI3K, STAT3 and IL-6 in the knee joint homogenate. TREM-1 levels showed the greatest reduction with the combination therapy. Furthermore, improvement was noted in oxidative stress markers with an increase in non-protein thiols and a decrease in malondialdehyde. In conclusion, the current study shows a therapeutic potential effect of combining metformin and pravastatin in OA, which could be partly attributed to TREM-1 signaling pathway.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s10787-025-01738-6","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T18:54:34Z","timestamp":1746298474000},"page":"2737-2748","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting TREM-1 receptors with metformin and pravastatin modulate monosodium iodoacetate-induced osteoarthritis"],"prefix":"10.1007","volume":"33","author":[{"given":"Eman R.","family":"Al Sawy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7916-7863","authenticated-orcid":false,"given":"Mona M.","family":"Saber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noha N.","family":"Nassar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrine S. 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