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Analysis of previously published RNA-seq datasets identified the ectodysplasin-A2 receptor (EDA2R), an X-linked member of the TNF-receptor superfamily, as a candidate regulator of this process. This study was conducted to test the hypothesis that the EDA-A2\/EDA2R axis is a regulator that directly regulates sperm capacitation during fertilization process. Western blotting and immunofluorescence showed that EDA2R was localized in late spermatogenic cells and in the midpiece of epididymal sperm. Incubation of mouse sperm in HTF medium containing the corresponding ligand EDA-A2 (0\u20131\u00a0\u00b5g\/mL) resulted in a dose-dependent improvement in the amplitude of lateral head displacement and curvilinear velocities. Ligand exposure promoted the appearance of capacitation hallmarks: tyrosine phosphorylation level was elevated within 30\u00a0min and the proportion of FITC-PNA positive, acrosome-reacted cells increased at 30 and 60\u00a0min (p\u2009&lt;\u20090.05). The EDA-A2 treated sperm yielded a higher cleavage rate (78.5% vs. 48.3%) and a higher blastocyst formation rate (97.6% vs. 88.4%) after in vitro fertilization. qPCR in hormonally synchronized females revealed transient ovarian and prolonged oviductal\n                    <jats:italic>Eda-a2<\/jats:italic>\n                    upregulation surrounding ovulation, suggesting that the ligand is present at the site of sperm-oocytes fertilization. These results clarify that EDA-A2\/EDA2R is a rapid physiological driver of sperm capacitation. This provides a tractable cytokine axis for optimizing assisted reproduction.\n                  <\/jats:p>","DOI":"10.1007\/s11626-025-01084-5","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T20:10:59Z","timestamp":1753128659000},"page":"1017-1026","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functions of ectodysplasin A2 receptor (EDA2R) in inducing capacitation of sperm in mice"],"prefix":"10.1007","volume":"61","author":[{"given":"Oluwakemi I.","family":"Anjorin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9234-4289","authenticated-orcid":false,"given":"Takahiro","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6500-2088","authenticated-orcid":false,"given":"Masayuki","family":"Shimada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"1084_CR1","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1055\/s-0042-1759630","volume":"44","author":"F Adanac\u0131oglu","year":"2022","unstructured":"Adanac\u0131oglu F, \u00c7etin \u00c7, Tokat G et al (2022) Comparison of the effects of GMCSF-containing and traditional culture media on embryo development and pregnancy success rates. 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