Decoding premature ovarian insufficiency: the role of histone family genes and their diagnostic potential

Abstract Background Premature ovarian insufficiency (POI) diagnostics are currently constrained by a limited understanding of its molecular underpinnings. While clinical assessment relies primarily on hormonal profiling and ultrasonography, the inherent genetic heterogeneity and complex etiology of POI necessitate the identification of robust genomic biomarkers to clarify pathogenesis and improve early detection. Main body This integrative bioinformatic analysis examines the genetic andscape of POI through multi-cohort expression profiling. We performed weighted gene co-expression network analysis and differential expression screening across aggregated ovarian datasets to identify convergent pathogenic signals. Functional enrichment analysis revealed a significant association with systemic lupus erythematosus pathways and chromatin organization centered on centromere protein A variant nucleosomes. Protein interaction network construction pinpointed a tightly interconnected cluster of histone family members and some other genes, including HIST1H4F(H4C6), HIST1H4K (H4C12), HIST1H2AK (H2AC13), HIST1H4H (H4C11), HIST1H2AJ (H2AC14), RNF213, STAT2, MT1E, and MT1A as central hub genes. Subsequent immune infiltration assessment demonstrated a preferential correlation between these histone transcripts and naive B cell populations. Cross-species validation using murine ovarian transcriptomic data provided orthogonal support for the dysregulation of this histone axis. Furthermore, receiver operating characteristic analysis indicated that HIST1H4F exhibited the most promising discriminatory capacity among the candidate genes, with its potential signaling involvement linked to the retinoic acid-inducible gene I-like receptor pathway. Conclusion This exploratory investigation implicates a specific repertoire of histone family genes as critical molecular participants in POI pathophysiology, with HIST1H4F emerging as a notable candidate for further diagnostic evaluation. The findings underscore the necessity of transitioning from purely descriptive genetics to functional validation in human peripheral samples. Future research must focus on longitudinal profiling of these chromatin regulators to determine their clinical utility in guiding patient stratification and monitoring ovarian reserve dynamics.