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Macrophages and immunometabolism in diminished ovarian reserve: pathological features and therapeutic implications

Year: 2026
Type: review
Abstract: Diminished ovarian reserve (DOR) is a prevalent reproductive endocrine disorder that significantly impairs female fertility. While traditional research has emphasized intrinsic oocyte defects, growing evidence highlights the ovarian immune microenvironment-specifically macrophages-as a critical regulator of follicular fate and reserve maintenance. Nevertheless, the mechanisms by which macrophage dysfunction drives DOR remain incompletely understood, and the interplay between chronic inflammation and macrophage metabolic reprogramming has yet to be systematically elucidated. This narrative review synthesizes literature from immunology, metabolism, and reproductive medicine, framing current evidence as established findings, putative mechanisms, and emerging hypotheses. The key findings are threefold: 1) macrophage polarization imbalance, which is marked by sustained M1 activation and impaired M2 function, constitutes a core pathological feature of DOR; 2) this imbalance is driven by metabolic reprogramming-specifically, metabolic inflexibility in M1 (persistent glycolytic commitment) and suppressed oxidative phosphorylation in M2-which links inflammaging to ovarian fibrosis and follicular depletion; and 3) pharmacological modulation of macrophage immunometabolism (e.g., AMPK/PPARγ activators, LXR agonists, and itaconate) and engineered delivery platforms (e.g., exosomes and targeted nanocarriers) hold preclinical promise. This review establishes an "immunometabolic axis" framework that integrates macrophage polarization, metabolic dysregulation, and ovarian reserve loss, advancing the understanding of DOR pathogenesis and informing precision interventions.
DOI: 10.3389/fendo.2026.1883984
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7220374382
FWCI:
Cites: 159
Cited by:
Related to: 10