Mechanistic Insights Into Recurrent Implantation Failure: The Lactate– H3K18la – SLC7A11 Axis Explored via Endometrial Organoid and Blastoid–Endometrial Cell Implantation Models

Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technologies, with the underlying molecular mechanisms still largely unknown. Here, we conducted proteomic profiling and analysed publicly available single‐cell RNA sequencing data, revealing a marked decrease in lactate dehydrogenase A (LDHA) expression in RIF cases. While traditionally considered a metabolic byproduct, it is now recognised to play a role in signalling and epigenetic regulation. Utilising human endometrial organoids, we demonstrated that lactate enhances human endometrial receptivity by promoting epithelial–mesenchymal transition (EMT) and upregulating histone H3 lysine 18 lactylation (H3K18la). Further multi‐omics analyses identified solute carrier family 7 member 11 ( SLC7A11 ) as an H3K18la‐regulated target. Functional assays confirmed that lactate‐induced H3K18la upregulates SLC7A11 , thereby driving EMT and cellular migration. Notably, using a blastoid–endometrial cell implantation model, we demonstrated that SLC7A11 promotes both blastoid adhesion and expansion, highlighting its critical role in embryo–endometrial interactions. Collectively, leveraging multiple organoid systems, including endometrial organoids and blastoid–endometrial cell implantation models, our findings reveal a novel lactate–H3K18la–SLC7A11 axis that orchestrates endometrial epithelial plasticity and receptivity. In addition, this study established a robust methodological framework for investigating implantation mechanisms.