{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T05:14:38Z","timestamp":1788671678320,"version":"build-2803163510"},"reference-count":103,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32370915"],"award-info":[{"award-number":["32370915"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32171114"],"award-info":[{"award-number":["32171114"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["32370915"],"award-info":[{"award-number":["32370915"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["32171114"],"award-info":[{"award-number":["32171114"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Successful embryo implantation requires intimate crosstalk between the blastocyst and the uterine epithelium within a defined window of receptivity. However, the metabolic signals that mediate this process in mammals remain poorly understood. In this study, pregnant mice, primary uterine cell culture and uterine epithelial organoids were used to examine the regulation and function of heme oxygenase-1 (HO-1) during mouse embryo implantation and decidualization. We demonstrate that embryo-derived lactic acid drives heme catabolism and regulates epithelial receptivity in mice through a hypoxia-inducible factor 1\u03b1 (HIF1\u03b1) -heme oxygenase-1 (HO-1) signaling axis. Specifically, lactic acid stabilizes HIF1\u03b1 to induce HO-1 expression in uterine epithelial cells by promoting von Hippel-Lindau (VHL) nucleolar sequestration and downregulating PHD2\/3. Additionally, lactic acid suppresses the transcriptional repressor BACH1, further facilitating HO-1 induction. At physiological heme levels, HO-1-derived bilirubin promotes epithelial receptivity by increasing phosphorylated STAT3 (p-STAT3) and downregulating MUC1. A low dose of hemin promotes epithelial receptivity and decidualization, whereas a high dose of hemin suppresses these processes. Pharmacological inhibition of HO-1 in mice markedly reduces implantation sites, establishing the functional necessity of this pathway. However, when heme levels exceed the regulatory capacity of HO-1, epithelial dysfunction ensues, characterized by reduced p-STAT3 and elevated MUC1, which ultimately disrupts implantation. Consistent with this, chronic heme exposure by oral gavage in mice increases uterine heme levels and upregulates BACH1, thereby suppressing HO-1 and trapping the uterus in a non-receptive state, causing implantation failure. Our findings define a lactic acid-HIF1\u03b1-HO-1-heme metabolic checkpoint that couples glycolytic signaling to heme regulation and endometrial receptivity. Dysregulation of this checkpoint may contribute to implantation disorders associated with heme stress, providing mechanistic insights into heme stress-related uterine receptivity failure.<\/jats:p>","DOI":"10.3390\/antiox15091114","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:50:44Z","timestamp":1788529844000},"page":"1114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blastocyst-Derived Lactic Acid Regulates Uterine Epithelial Receptivity and Stromal Decidualization via the HIF1\u03b1-HO-1-Heme Metabolic Axis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9474-8414","authenticated-orcid":false,"given":"Wen-Xu","family":"Yao","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3333-1337","authenticated-orcid":false,"given":"Yao-Dan","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Yao","family":"Ding","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Lan","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6016-5710","authenticated-orcid":false,"given":"Zeng-Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ochoa-Bernal, M.A., and Fazleabas, A.T. 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