Journal of assisted reproduction and genetics · 2026
LSD1-ESM1 regulates extravillous trophoblast function through metabolic reprogramming in recurrent spontaneous abortion.
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Tang Xiaoxia, Xu Tianhan, Zhang Qinyi, Lin Shi, Du Hongxiang, Wu Sufang, Zhang Jiawen
Аннотация
BACKGROUND: The pathological mechanisms of recurrent spontaneous abortion (RSA) are closely linked to dysfunction of extravillous trophoblasts (EVTs), yet the underlying epigenetic regulation remains unclear.
METHODS: Cell proliferation, migration, invasion, and apoptosis were assessed using CCK-8, wound healing, Transwell, and flow cytometry assays. Pharmacological interventions were performed using the LSD1 inhibitor ORY-1001 in combination with metformin. Western blotting, qRT-PCR, RNA sequencing, and chromatin immunoprecipitation were employed to elucidate the molecular mechanism by which LSD1 regulates trophoblast function.
RESULTS: Our analyses revealed that LSD1 expression was markedly reduced in villous tissues from RSA patients, predominantly within the EVT subpopulation. Functional assays demonstrated that LSD1 knockdown suppressed EVT proliferation, migration, and invasion, whereas its overexpression enhanced these capabilities. Multi-omics analyses revealed that LSD1 downregulation induced broad disturbances in glucose and lipid metabolism, leading to an insulin resistance-like phenotype. Mechanistically, LSD1 promotes ESM1 transcription by binding to specific regulatory regions of the ESM1 gene and catalyzing H3K9me2 demethylation, thereby regulating EVT function through ESM1-mediated modulation of EGFR/STAT3 and IR signaling pathways. Clinical validation confirmed that the LSD1-ESM1-p-STAT3 axis was coordinately downregulated in RSA patients. Additionally, metformin partially rescued resorption rates induced by LSD1 inhibition in mice.
CONCLUSION: This study reveals a role of epigenetic-metabolic coupling in the pathogenesis of pregnancy loss. It identifies a potential molecular target and mechanistic basis for the diagnosis and treatment of RSA.
METHODS: Cell proliferation, migration, invasion, and apoptosis were assessed using CCK-8, wound healing, Transwell, and flow cytometry assays. Pharmacological interventions were performed using the LSD1 inhibitor ORY-1001 in combination with metformin. Western blotting, qRT-PCR, RNA sequencing, and chromatin immunoprecipitation were employed to elucidate the molecular mechanism by which LSD1 regulates trophoblast function.
RESULTS: Our analyses revealed that LSD1 expression was markedly reduced in villous tissues from RSA patients, predominantly within the EVT subpopulation. Functional assays demonstrated that LSD1 knockdown suppressed EVT proliferation, migration, and invasion, whereas its overexpression enhanced these capabilities. Multi-omics analyses revealed that LSD1 downregulation induced broad disturbances in glucose and lipid metabolism, leading to an insulin resistance-like phenotype. Mechanistically, LSD1 promotes ESM1 transcription by binding to specific regulatory regions of the ESM1 gene and catalyzing H3K9me2 demethylation, thereby regulating EVT function through ESM1-mediated modulation of EGFR/STAT3 and IR signaling pathways. Clinical validation confirmed that the LSD1-ESM1-p-STAT3 axis was coordinately downregulated in RSA patients. Additionally, metformin partially rescued resorption rates induced by LSD1 inhibition in mice.
CONCLUSION: This study reveals a role of epigenetic-metabolic coupling in the pathogenesis of pregnancy loss. It identifies a potential molecular target and mechanistic basis for the diagnosis and treatment of RSA.