Nfkb1 Loss Accelerates Follicle Depletion via Ovarian Inflammation in Mice

The Monash preclinical study measured follicle counts, inflammatory markers, and reproductive lifespan in Nfkb1-null mice versus wild-type controls. Females lacking the gene showed accelerated depletion of primordial and growing follicles, higher ovarian cytokine levels, and earlier cessation of fertility compared with controls. These changes occurred without external stressors, indicating that baseline NF-ĸB1 activity normally restrains low-grade inflammaging within the ovary. Human premature ovarian insufficiency already carries documented risks of cardiovascular disease and osteoporosis; the mouse data suggest inflammation may be a modifiable upstream driver rather than a secondary consequence. Prior genetic screens for POI have identified only a handful of loci; NFKB1 was not among them, so the finding expands the candidate list for targeted sequencing panels. Next steps require case-control sequencing of NFKB1 and related pathway genes in women with idiopathic POI plus functional assays of identified variants in human granulosa cells.