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Occurring in mammals that develop invasive hemochorial placentae, decidualization is a pivotal evolutionary adaptation in mammals that supports pregnancy establishment, implantation, and placentation in a limited number of animal species. During decidualization, an endometrial stromal cell undergoes profound genetic, epigenetic, and proteomic changes, allowing it to prevent immunological rejection and fostering the development of a newly implanted embryo. To tolerate the cellular reprogramming that occurs during decidualization, a stromal cell must withstand reactive oxygen species (ROS), inflammation, and oxidative stress associated with this process. This review focuses on key events that have allowed decidualization to tolerate high levels of oxidative stress during early pregnancy, creating a specialized maternal\u2013fetal interface and allowing for deep placentation. We focus on the features that allowed certain eutherian mammals to develop strong, progesterone (P4)-driven decidualization that resists antioxidant stress and confers cellular resilience. We also discuss how these oxidative stress responses are implicated in reproductive disorders such as endometriosis and recurrent pregnancy loss, underscoring their clinical relevance. We examine known molecular players that work to collectively mitigate oxidative stress from ROS and we highlight the emerging roles of SLC40A1 and GPX4 in coordinating iron balance and mitigating lipid peroxidation to enhance endometrial decidualization. By highlighting the key mechanistic adaptations of endometrial stromal cells at the maternal\u2013fetal interface, we emphasize the importance of mitigating oxidative stress for successful pregnancy establishment and reproductive health.<\/jats:p>","DOI":"10.1093\/biolre\/ioaf198","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T10:24:34Z","timestamp":1756808674000},"page":"511-530","source":"Crossref","is-referenced-by-count":9,"title":["Mechanisms driving resistance to oxidative stress during endometrial stromal cell decidualization"],"prefix":"10.1093","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0486-2305","authenticated-orcid":false,"given":"Rupak","family":"Thapa","sequence":"first","affiliation":[{"name":"Center for Drug Discovery, Baylor College of Medicine , Houston, Texas ,","place":["United States"]},{"name":"Department of Pathology and Immunology, Baylor College of Medicine , Houston, Texas ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5660-6392","authenticated-orcid":false,"given":"Diana","family":"Monsivais","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery, Baylor College of Medicine , Houston, Texas ,","place":["United States"]},{"name":"Department of Pathology and Immunology, Baylor College of Medicine , Houston, Texas ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"2026041420171924400_ref1","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.3390\/cells13151236","article-title":"Unraveling the dynamics of estrogen and progesterone signaling in the endometrium: an overview","volume":"13","author":"Dias Da Silva","year":"2024","journal-title":"Cells"},{"key":"2026041420171924400_ref2","first-page":"285","article-title":"The physiology of the 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