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In the venoms of species clinically associated with accidents, phospholipases D (PLDs) are the most expressed toxins. This classification is based on the toxins\u2019 ability to cleave various phospholipids, with a preference for sphingomyelin. Studies using purified PLDs have demonstrated that these enzymes cleave phospholipids from cells, producing derivatives that can activate leukocytes. A dysregulated inflammatory response is the primary effect following envenomation, leading to dermonecrosis, which is histopathologically characterized by aseptic coagulative necrosis\u2014a key feature of envenomation. Although advances in understanding the structure\u2013function relationship of enzymes have been achieved through molecular biology, heterologous expression, site-directed mutations, crystallography, and bioinformatic analyses\u2014describing PLDs in the venoms of various species and highlighting the conservation of amino acid residues involved in catalysis, substrate binding, and magnesium stabilization\u2014little is known about the cellular biology of these PLDs. Studies have shown that the treatment of various cells with recombinant PLDs stimulates the formation of ectosomes and ectocytosis, events that initiate a cascade of intracellular signaling in PLD-binding cells and lead to the release of extracellular microvesicles. These microvesicles may act as signalosomes for other target cells, thereby triggering an inflammatory response and dermonecrosis. In this review, we will discuss the biochemical properties of PLDs, the target cells that bind to them, and the ectocytosis-dependent pathophysiology of envenoming.<\/jats:p>","DOI":"10.3390\/toxins17020070","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T05:50:36Z","timestamp":1738734636000},"page":"70","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Brown Spider Venom Phospholipases D: From Potent Molecules Involved in Pathogenesis of Brown Spider Bites to Molecular Tools for Studying Ectosomes, Ectocytosis, and Its Applications"],"prefix":"10.3390","volume":"17","author":[{"given":"Ana Carolina Martins","family":"Wille","sequence":"first","affiliation":[{"name":"Department of Structural, Molecular Biology and Genetics, State University of Ponta Grossa (UEPG), Ponta Grossa 84030-900, Brazil"},{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81530-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Izabele","family":"Machado","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81530-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4082-9249","authenticated-orcid":false,"given":"Samira Hajjar","family":"Souza","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81530-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna C\u00e2mara da","family":"Justa","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81530-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8396-5065","authenticated-orcid":false,"given":"Maria Eduarda de","family":"Fraga-Ferreira","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81530-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eloise de Souza","family":"Mello","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81530-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiza Helena","family":"Gremski","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81530-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio Sanches","family":"Veiga","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81530-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"ref_1","unstructured":"Vetter, R.S., and Swanson, D.L. 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