HSD17B12 deficiency is associated with granulosa cell apoptosis and inflammatory transcriptomic signatures in experimental premature ovarian insufficiency models

Premature ovarian insufficiency (POI) remains a challenging condition with largely elusive etiology. Granulosa cell (GC) apoptosis is a key event in follicular atresia. This study investigates the correlation between 17β-hydroxysteroid dehydrogenase type 12 (HSD17B12) expression and ovarian dysfunction, specifically examining the transcriptomic landscape associated with HSD17B12 modulation. A Tripterygium wilfordii polyglycoside suspension-induced POI mouse model was established to assess ovarian developmental status and Hsd17b12 expression. HSD17B12 was overexpressed or knocked down in human granulosa tumor (KGN) and ovarian adenocarcinoma (SKOV3) cell lines. Transcriptomic sequencing was performed to analyze differential gene expression. Both mRNA and protein levels of Hsd17b12 were significantly downregulated in the ovaries of the POI mouse model. In vitro, knockdown of HSD17B12 suppressed cell proliferation and exacerbated apoptosis in both cell models. Transcriptomic analysis revealed that differentially expressed genes (DEGs) were predominantly enriched in immune regulation and inflammatory response pathways. Specifically, HSD17B12 deficiency led to the significant upregulation of genes involved in the "Cytokine-cytokine receptor interaction" and the "NF-κB signaling pathway". HSD17B12 regulates proliferation and apoptosis in granulosa-like KGN cells, and HSD17B12 deficiency is associated with an inflammatory transcriptomic signature in experimental POI models.