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Despite the knowledge of envenomation\u2019s pathogenesis, the impact of <jats:italic>Crotalus<\/jats:italic> venom on adipose tissue (AT) cells is unknown. AT is an endocrine organ capable of releasing diverse immunomodulatory molecules, including prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>). Herein, we investigated the effects of <jats:italic>Crotalus durissus terrificus<\/jats:italic> venom (CdtV) on preadipocytes in vitro, focussing on the release of PGE<jats:sub>2<\/jats:sub> and mechanisms involved. CdtV (5 and 10\u00a0\u03bcg\/mL) induced a marked release of PGE<jats:sub>2<\/jats:sub> by preadipocytes (3\u201324\u00a0h) compared to controls. Pre-treatment of cells with SC-560 or NS-398, selective inhibitors for cyclooxygenase (COX)-1 and COX-2 enzymes, respectively, decreased CdtV-induced PGE<jats:sub>2<\/jats:sub> release after 24\u00a0h. CdtV (1 and 10\u00a0\u03bcg\/mL) did not change COX-1 protein expression by preadipocytes, but induced COX-2 protein expression at all time intervals evaluated. Pre-treating preadipocytes with AH6809, an inhibitor of the PGE<jats:sub>2<\/jats:sub> EP2 receptor, significantly increased the CdtV-induced PGE<jats:sub>2<\/jats:sub> release. EP1, EP3, or EP4 receptor antagonists did not change the CdtV-induced PGE<jats:sub>2<\/jats:sub> release. Additionally, CdtV did not alter the EP2 receptor protein expression in preadipocytes. These findings demonstrate that CdtV activates preadipocytes to produce PGE<jats:sub>2<\/jats:sub> via COX-1 activation and COX-2 protein expression and PGE<jats:sub>2<\/jats:sub> triggers a negative feedback loop via EP2 for its own production. These results highlight AT as another target for CdtV that may contribute to envenomation.<\/jats:p>","DOI":"10.1007\/s00204-025-04109-w","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T15:18:40Z","timestamp":1750691920000},"page":"4281-4289","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Crotalus durissus terrificus snake venom activates 3T3-L1 preadipocytes to release PGE2, which depends on COX-2 expression and is modulated by PGE2 EP2 receptor"],"prefix":"10.1007","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7601-5191","authenticated-orcid":false,"given":"Danilo Santos","family":"Teixeira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0630-8316","authenticated-orcid":false,"given":"Rodrigo","family":"Maia-Marques","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5887-7663","authenticated-orcid":false,"given":"Catarina","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"4109_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2023.107300","author":"FG Baudou","year":"2023","unstructured":"Baudou FG, Guti\u00e9rrez JM, Rodr\u00edguez JP (2023) Immune response to neurotoxic South American snake venoms. 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