Colony-stimulating factor-1 as a potential therapeutic target in asthenozoospermia

Background: Asthenozoospermia (AZS), a common cause of male infertility, is characterized by significantly reduced sperm motility, though its precise etiology remains unclear. Recent research highlights seminal plasma proteins' critical role in regulating sperm function. Colony-stimulating factor 1 (CSF-1), an essential cytokine for immune regulation and cell proliferation, has been implicated in sperm functional regulation, spermatogenesis, and maturation.

Methods: Seminal plasma samples from healthy men and AZS patients were collected using density-gradient centrifugation. Proteomics-based data-independent acquisition (DIA) identified four differentially expressed proteins: CD40, CSF-1, MCP-1, and IL-20. To provide an exploratory, proof-of-concept verification before large-scale validation. Subsequent validation in an independent small cohort confirmed a robust association between elevated seminal plasma CSF-1 levels and AZS. An in vitro sperm culture system assessed CSF-1's function of sperm from AZS patients were treated with the CSF-1 inhibitor Pexidartinib, while recombinant CSF-1 was supplemented in sperm from healthy donors.

Results: Pexidartinib treatment significantly increased sperm motility in AZS patients, whereas recombinant CSF-1 supplementation significantly reduced motility in healthy donor sperm. CSF-1 inhibition elevated intracellular ATP levels, suggesting disruption of mitochondrial energy metabolism as the mechanism for impaired motility. Proteomic profiling and functional assays demonstrated that seminal plasma CSF-1 induces mitochondrial dysfunction, thereby decreasing sperm motility.

Conclusion: Seminal-plasma CSF-1 is a potential pathogenic factor in AZS. Its overexpression suppresses sperm motility by impairing mitochondrial energy metabolism. CSF-1 represents both a diagnostic biomarker and a promising therapeutic target (e.g., via Pexidartinib) for the clinical management of AZS. These findings provide a foundation for novel diagnostic and therapeutic strategies.

Asthenozoospermia; CSF-1; Mitochondrial energy metabolism; Seminal-plasma protein.