Exploratory analysis of impaired pregnancy outcomes after preimplantation genetic testing and BNIP3L-related endometrial alterations in diminished ovarian reserve

Abstract Patients with diminished ovarian reserve (DOR) may have impaired pregnancy outcomes after preimplantation genetic testing (PGT), but the associated BNIP3L-related endometrial signatures are unclear. We analyzed three independent cohorts: (1) a retrospective PGT cohort ( n = 313) comparing pregnancy outcomes between DOR and normal ovarian reserve (NOR); (2) a peripheral-blood transcriptomic cohort ( n = 20); and (3) an endometrial immunohistochemistry cohort ( n = 10). We also performed BNIP3L virtual perturbation using single-cell transcriptomic data (GSE111976). Among patients undergoing euploid embryo transfer after PGT, those with DOR ( n = 67) had a lower ongoing pregnancy rate than those with NOR ( n = 246). Patients with DOR had higher peripheral-blood senescence scores, and BNIP3L was identified as a mitophagy- and senescence-associated candidate. Endometrial immunohistochemistry showed lower BNIP3L expression and a mosaic-like estrogen receptor 1 (ESR1) pattern in patients with DOR. Exploratory field-level correlation analysis suggested coexisting alterations in BNIP3L, p16, and ESR1 expression patterns within the endometrium. Virtual perturbation predicted differential regulation of CDKN2A and CXCL6 after BNIP3L reduction. These observational findings support a testable hypothesis linking BNIP3L-related endometrial signatures to DOR-associated reproductive failure and warrant prospective functional validation.