Integrated follicular fluid multi-omics identifies steroidogenic dysregulation and a candidate SHBG-associated rescue framework in poor ovarian response

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Introduction: Poor ovarian response (POR) remains a major obstacle in assisted reproductive technology, yet the follicular microenvironmental determinants of impaired ovarian sensitivity are poorly understood. This study aimed to characterize the multi_omics landscape of the follicular fluid in POR and to explore potential therapeutic candidates and underlying mechanisms. Methods: We performed 16S rRNA sequencing and untargeted metabolomics on follicular fluid samples from 26 women with POR and 25 normoresponsive controls. Integrated cross_omics analysis, exploratory modelling, and age_adjusted sensitivity assessments were conducted. Candidate metabolites identified by MS/MS annotation were tested in a Tripterygium glycoside_induced ovarian injury mouse model, with subsequent ovarian RNA sequencing, molecular docking, molecular dynamics simulation, qPCR, and SHBG immunohistochemistry to interrogate downstream pathways. Results: POR was associated with reduced microbial diversity, 55 differential metabolic features, and convergence of 16S_based and metabolomic signals on ABC transporter_related pathways. Age_adjusted analyses indicated that the metabolomic component was more robust than the 16S community_level findings, which are interpreted as exploratory. Two downregulated metabolites --Harmalol and Beraprost --were prioritized for in vivo intervention. Both candidates partially restored follicle counts, reduced ovarian apoptosis, and improved LH/FSH profiles. Mechanistic investigations nominated an SHBG_associated steroidogenic program as a candidate downstream effector. Discussion: These findings support a working model wherein follicular microenvironment remodelling in POR converges on steroidogenic dysregulation, providing testable rescue hypotheses. The results highlight the relative robustness of metabolomic signatures over microbiome shifts in this context, though further functional validation is required to confirm causality and therapeutic potential.

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