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Calcium homeostasis is pivotal for its asexual reproduction in mammalian host cells, and sarcoendoplasmic reticulum calcium-ATPase (SERCA) is considered vital for maintaining ion homeostasis within the parasite. This work studied the physiological relevance, structure-function relationship, mechanism, and therapeutic value of SERCA in the acutely-infectious tachyzoite stage of <jats:italic>T. gondii<\/jats:italic>. A conditional depletion of SERCA, located in the endoplasmic reticulum, by auxin-inducible degradation is lethal for the parasite due to severe defects in its replication, gliding motility, and invasion. The observed phenotypes are caused by dysregulated calcium ion\u00a0homeostasis and microneme secretion in the absence of <jats:italic>Tg<\/jats:italic>SERCA. Furthermore, ectopic expression of <jats:italic>Tg<\/jats:italic>SERCA restored the lytic cycle of a phosphatidylthreonine-null and phosphatidylserine-enriched mutant with perturbed calcium homeostasis, motility and invasion. These lipids are expressed in the parasite ER, co-localizing with <jats:italic>Tg<\/jats:italic>SERCA. Last but not least, the structure-function modeling and ligand docking of <jats:italic>Tg<\/jats:italic>SERCA with a library comprising &gt;5000 chemicals identified two compounds (RB-15, NR-301) that inhibited the lytic cycle by affecting the tachyzoite locomotion, invasion, microneme discharge, and calcium levels. In conclusion, we demonstrate <jats:italic>Tg<\/jats:italic>SERCA as an indispensable <jats:italic>lipid-assisted<\/jats:italic> calcium pump in <jats:italic>T. gondii<\/jats:italic> and report small molecules with therapeutic potential against toxoplasmosis.<\/jats:p>","DOI":"10.1038\/s42003-025-08058-z","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T06:37:25Z","timestamp":1746513445000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sarcoendoplasmic reticulum calcium ATPase is an essential and druggable lipid-dependent ion pump in Toxoplasma gondii"],"prefix":"10.1038","volume":"8","author":[{"given":"Rosalba","family":"Cruz-Mir\u00f3n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namita","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Alexandros Katelas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arunakar","family":"Kuchipudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharmarajan","family":"Sriram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Gangopadhyay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7384-690X","authenticated-orcid":false,"given":"Soumyananda","family":"Chakraborti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratnesh Kumar","family":"Srivastav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1452-5126","authenticated-orcid":false,"given":"Nishith","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"8058_CR1","doi-asserted-by":"publisher","first-page":"805","DOI":"10.3109\/00365548.2012.693197","volume":"44","author":"G Saadatnia","year":"2012","unstructured":"Saadatnia, G. & Golkar, M. 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