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Network-based approaches, unlike those focused solely on direct targets, effectively detect a wide range of cellular responses elicited by compounds. This study applied protein covariation network analysis, leveraging quantitative, morphological, and localization features from immunostained microscopic images, to elucidate the MoA of AX-53802, a novel ferroptosis inducer. From the candidate targets extracted through network analysis, GPX4 was verified as the direct target by validation experiments. Additionally, aggregates involving GPX4, TfR1, and F-actin were observed alongside iron reduction, suggesting a ferroptosis defense mechanism. Furthermore, combination therapies targeting GPX4 and FAK\/Src were found to enhance cancer cell death, and MDM2, ezrin, and cortactin were identified as potential ferroptosis inhibitor targets. These findings highlight the effectiveness of network-based approaches in uncovering a compound\u2019s MoA and developing combination therapies for cancer.<\/jats:p>","DOI":"10.1038\/s42003-025-07886-3","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T05:10:35Z","timestamp":1743397835000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0343-9735","authenticated-orcid":false,"given":"Rina","family":"Kunishige","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Noguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8518-2813","authenticated-orcid":false,"given":"Akito","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Murata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1903-8733","authenticated-orcid":false,"given":"Fumi","family":"Kano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"7886_CR1","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/j.cell.2015.05.056","volume":"162","author":"J. 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