Inflammatory Remodeling of the Ovarian Microenvironment in Premature Ovarian Insufficiency

Premature ovarian insufficiency (POI) is increasingly recognized as a disorder shaped not only by follicle-intrinsic defects but also by disruption of the ovarian tissue microenvironment. This perspective reframes POI as a process of inflammatory ovarian remodeling, in which immune activation, macrophage polarization, mitochondrial stress, inflammasome signaling, and inflammatory regulated cell death interact to accelerate follicular injury and ovarian reserve decline.

Rather than providing a pathway-by-pathway summary, the authors highlight a stepwise model linking upstream genetic, iatrogenic, autoimmune, oxidative, and metabolic insults to immune-cell remodeling, granulosa cell dysfunction, oocyte damage, and follicular loss. Particular attention is given to the macrophage–mitochondria–NLRP3 axis and to the emerging role of pyroptosis and ferroptosis as amplifiers of ovarian inflammation.

The review discusses how cell-based therapy, metabolic intervention, mitochondrial protection, inflammasome inhibition, and ferroptosis blockade may restore microenvironmental homeostasis. These potential therapeutic strategies target specific inflammatory pathways identified in the proposed model to mitigate follicular damage and preserve ovarian function.

Current evidence remains largely preclinical, with significant gaps in human data. The authors emphasize that human samples, spatial omics, and longitudinal studies are needed to validate inflammatory remodeling programs across different POI subtypes before clinical translation can occur.