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Background <p>Autoimmune abnormalities are increasingly recognized as contributing factors to unexplained infertility. Among these, antinuclear antibodies (ANAs) are the most frequently detected autoantibodies and have been associated with adverse embryologic outcomes. However, the mechanisms by which isolated ANA positivity (defined as ANA positivity in the absence of anti–extractable nuclear antigen [anti-ENA] antibodies) may influence oocyte developmental competence and early embryonic development remain poorly understood. This study aimed to characterize follicular fluid (FF) molecular alterations associated with isolated ANA positivity using an integrative multi-omics approach.</p> Methods <p>In this prospective cohort study, 70 infertile women undergoing their first assisted reproductive technology (ART) cycle were enrolled, including 32 women with isolated ANA positivity (serum ANA ≥ 1:80 and anti-ENA negative) and 38 ANA-negative controls. FF samples collected on the day of oocyte retrieval were subjected to integrated metabolomic and proteomic analyses. Differential expression and functional enrichment analyses were performed, followed by correlation and network analyses to explore associations between FF molecular profiles and oocyte as well as embryo developmental competence. Key metabolites were further evaluated using receiver operating characteristic (ROC) analyses to characterize their exploratory discriminatory performance.</p> Results <p>Women with isolated ANA positivity showed significantly poorer embryo developmental outcomes than ANA-negative controls, including lower IVF/ICSI fertilization rates and reduced numbers of high-quality embryos and blastocysts (all <i>P &lt;</i> 0.05). After adjustment for potential confounders, multivariate linear regression analysis suggested that isolated serum ANA positivity was independently associated with impaired early embryonic development (<i>P &lt;</i> 0.05). Integrated multi-omics analyses revealed significant dysregulation of pathways related to steroid hormone biosynthesis, immune-related pathways including complement and coagulation cascades, amino acid metabolism, and glycerophospholipid metabolism. Among the identified molecular features, three metabolites—L-phenylalanine, SM(d18:1/16:0), and hydrocortisone—were consistently associated with embryo developmental potential and showed stable correlations independent of ANA titers. A combined preliminary metabolite panel was identified that discriminates ANA-positive from ANA-negative women with excellent discriminatory performance (AUC = 0.968). In exploratory analyses of dichotomized oocyte- and early embryo–related outcomes, the panel showed moderate discriminatory performance (AUCs = 0.719–0.771).</p> Conclusions <p>Isolated ANA positivity is associated with metabolic reprogramming in the follicular microenvironment and impaired early embryonic development. The identified exploratory metabolite signatures provide insight into immune–metabolic alterations that may underlie ANA-associated infertility and may inform future prognostic model development. Their associations appeared consistent across the ANA-titer subgroups examined. However, the panel remains preliminary and at the discovery stage and requires validation in independent cohorts before its clinical relevance or utility can be determined.</p>

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Proteomic and metabolomic alterations in follicular fluid associated with embryological outcomes in women with isolated ANA-positive infertility: a prospective multi-omics cohort study

  • 期刊论文

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  • 发表日期：

    2026年8月1日

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  • Kai Ding,
  • Wei Jiang,
  • Yidan Chen,
  • Shanren Cao,
  • Xin Li,
  • Jiajia Yao,
  • Yi Wei,
  • Junqiang Zhang,
  • Xiufeng Ling,
  • Chun Zhao

摘要

Background

Autoimmune abnormalities are increasingly recognized as contributing factors to unexplained infertility. Among these, antinuclear antibodies (ANAs) are the most frequently detected autoantibodies and have been associated with adverse embryologic outcomes. However, the mechanisms by which isolated ANA positivity (defined as ANA positivity in the absence of anti–extractable nuclear antigen [anti-ENA] antibodies) may influence oocyte developmental competence and early embryonic development remain poorly understood. This study aimed to characterize follicular fluid (FF) molecular alterations associated with isolated ANA positivity using an integrative multi-omics approach.

Methods

In this prospective cohort study, 70 infertile women undergoing their first assisted reproductive technology (ART) cycle were enrolled, including 32 women with isolated ANA positivity (serum ANA ≥ 1:80 and anti-ENA negative) and 38 ANA-negative controls. FF samples collected on the day of oocyte retrieval were subjected to integrated metabolomic and proteomic analyses. Differential expression and functional enrichment analyses were performed, followed by correlation and network analyses to explore associations between FF molecular profiles and oocyte as well as embryo developmental competence. Key metabolites were further evaluated using receiver operating characteristic (ROC) analyses to characterize their exploratory discriminatory performance.

Results

Women with isolated ANA positivity showed significantly poorer embryo developmental outcomes than ANA-negative controls, including lower IVF/ICSI fertilization rates and reduced numbers of high-quality embryos and blastocysts (all P < 0.05). After adjustment for potential confounders, multivariate linear regression analysis suggested that isolated serum ANA positivity was independently associated with impaired early embryonic development (P < 0.05). Integrated multi-omics analyses revealed significant dysregulation of pathways related to steroid hormone biosynthesis, immune-related pathways including complement and coagulation cascades, amino acid metabolism, and glycerophospholipid metabolism. Among the identified molecular features, three metabolites—L-phenylalanine, SM(d18:1/16:0), and hydrocortisone—were consistently associated with embryo developmental potential and showed stable correlations independent of ANA titers. A combined preliminary metabolite panel was identified that discriminates ANA-positive from ANA-negative women with excellent discriminatory performance (AUC = 0.968). In exploratory analyses of dichotomized oocyte- and early embryo–related outcomes, the panel showed moderate discriminatory performance (AUCs = 0.719–0.771).

Conclusions

Isolated ANA positivity is associated with metabolic reprogramming in the follicular microenvironment and impaired early embryonic development. The identified exploratory metabolite signatures provide insight into immune–metabolic alterations that may underlie ANA-associated infertility and may inform future prognostic model development. Their associations appeared consistent across the ANA-titer subgroups examined. However, the panel remains preliminary and at the discovery stage and requires validation in independent cohorts before its clinical relevance or utility can be determined.