CSF3R signalling beyond granulopoiesis: new paradigms in female reproductive biology

The Colony-Stimulating Factor 3 Receptor (CSF3R), the receptor for granulocyte colony-stimulating factor (G-CSF), has expanded from a hematopoietic regulator to a multifunctional signalling molecule with significant relevance in gynaecological biology. High-resolution transcriptomic and proteomic studies now identify CSF3R expression in ovarian granulosa cells, endometrial epithelium, cervical tissue, placental trophoblasts, and gynaecologic tumour microenvironments, highlighting its integration into immune, endocrine, and tissue-remodeling networks. Structurally anchored by Box1/Box2 motifs, CSF3R initiates key intracellular pathways JAK-STAT, MAPK/ERK, PI3K-AKT-mTOR, SRC-family kinases, and Nf-κB governing cellular survival, proliferation, angiogenesis, metabolic activity, inflammation, and epithelial-mesenchymal transition. Dysregulated CSF3R signalling contributes to major gynaecological disorders. In polycystic ovary syndrome (PCOS), chronic inflammation and altered CSF3R-STAT3/Nf-κB activity disturb follicular maturation and endocrine-metabolic balance. In endometriosis, CSF3R-associated neutrophil activation, MMP induction, and ERK-driven angiogenesis sustain lesion growth and chronic pelvic inflammation. During implantation, defective CSF3R-mediated STAT3 signalling impairs decidualization, immune tolerance, and trophoblast invasion, contributing to implantation failure and recurrent pregnancy loss. In ovarian and endometrial cancers, CSF3R drives tumour proliferation, EMT, angiogenesis, and recruitment of immunosuppressive myeloid-derived suppressor cells. Therapeutically, targeting G-CSF3R-linked pathways offers emerging opportunities. Approaches include JAK inhibitors, PI3K/mTOR inhibitors, SRC inhibitors, STAT3 antagonists, and investigational anti-G-CSF/anti-CSF3R monoclonal antibodies. G-CSF therapy has also shown benefits in improving endometrial receptivity in select cases of reproductive failure. This review explored CSF3R biology, signalling, disease involvement, and therapeutic potential, positioning G-CSF3R as an emerging, actionable node in reproductive medicine and gynaecologic oncology.