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It leads to a plethora of cellular damage, including lipid peroxidation, DNA double-strand breaks (DNA DSBs), and breakdown of the mitochondrial membrane potential (MMP). We could show in several cell lines that <jats:italic>t<\/jats:italic>-BuOOH induces ferroptosis, triggered by iron-dependent lipid peroxidation. We have further revealed that not only <jats:italic>t<\/jats:italic>-BuOOH-mediated ferroptosis, but also DNA DSBs and loss of MMP are prevented by cell\u2013cell contacts. The underlying mechanisms are not known. Here, we show in murine fibroblasts and a human colon carcinoma cell line that <jats:italic>t<\/jats:italic>-BuOOH (50 or 100\u00a0\u00b5M, resp.) causes an increase in intracellular Ca<jats:sup>2+<\/jats:sup>, and that this increase is key to lipid peroxidation and ferroptosis, DNA DSB formation and dissipation of the MMP. We further demonstrate that cell\u2013cell contacts prevent <jats:italic>t<\/jats:italic>-BuOOH-mediated raise in intracellular Ca<jats:sup>2+<\/jats:sup>. Hence, we provide novel insights into the mechanism of <jats:italic>t<\/jats:italic>-BuOOH-triggered cellular damage including ferroptosis and propose a model in which cell\u2013cell contacts control intracellular Ca<jats:sup>2+<\/jats:sup> levels to prevent lipid peroxidation, DNA DSB-formation and loss of MMP. Since Ca<jats:sup>2+<\/jats:sup> is a central player of toxicity in response to oxidative stress and is involved in various cell death pathways, our observations suggest a broad protective function of cell\u2013cell contacts against a variety of exogenous toxicants.<\/jats:p>","DOI":"10.1007\/s00204-024-03792-5","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T07:07:29Z","timestamp":1717052849000},"page":"2953-2969","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cell\u2013cell contacts prevent t-BuOOH-triggered ferroptosis and cellular damage in vitro by regulation of intracellular calcium"],"prefix":"10.1007","volume":"98","author":[{"given":"Dagmar","family":"Faust","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Wenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Holm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Harms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Greffrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5250-6324","authenticated-orcid":false,"given":"Cornelia","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"issue":"Pt 3","key":"3792_CR1","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1042\/0264-6021:3570593","volume":"357","author":"WK Alderton","year":"2001","unstructured":"Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. 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