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

Wang et al. Reproductive Biology and Endocrinology https://doi.org/10.1186/s12958-025-01476-y Reproductive Biology and Endocrinology (2025) 23:135 Open Access RESEARCH Colony-stimulating factor-1 as a potential therapeutic target in asthenozoospermia Yongyong Wang1†, Qi Zhou2†, Cong Huang3†, Xiaodong Li2, Haining Liu1†, Zhongyi Sun4† and Baoquan Han1,4*† Abstract 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. Keywords Asthenozoospermia, Seminal-plasma protein, CSF-1, Mitochondrial energy metabolism † Yongyong Wang, Qi Zhou and Cong Huang contributed equally to this work. † Haining Liu, Zhongyi Sun and Baoquan Han co-corresponding authors. *Correspondence: Baoquan Han 1 Department of Reproductive Medicine, Qingdao Municipal Hospital, Qingdao, Shandong, China 2 The First Affiliated Hospital of Henan University, Henan University, Kaifeng, China 3 Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, China 4 Department of Urology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China © The Author(s) 2025. 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To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Wang et al. Reproductive Biology and Endocrinology (2025) 23:135 Introduction Asthenozoospermia (AZS) is a common cause of male infertility, accounting for approximately 40% to 50% of all cases reported worldwide the condition is defined by a marked reduction in progressive sperm motility. According to the World Health Organization (WHO) Laboratory Manual for the Examination and Processing of Human Semen, AZS is diagnosed when the proportion of sperm exhibiting progressive motility (PR) is less than 32% or when the combined percentage of progressive and non-progressive motile sperm (PR + NP) is less than 40%. One of the primary challenges to natural fertility is the reduced motility of sperm, which is unable to penetrate the cervical mucous barrier or reach the oviduct to fertilize the oocyte [1]. The frequent co-occurrence of AZS with other semen abnormalities, such as oligozoospermia and teratozoospermia, further exacerbates subfertility [2, 3]. In addition to its direct impact on fecundity, AZS has far-reaching consequences for both individuals and families, as it adversely affects psychological well-being and quality of life. AZS is a disorder that is highly complex and heterogeneous, involving multiple etiological factors, including genetic predisposition, environmental stressors, endocrine disruptors, and lifestyle behaviors. The pathogenesis of this disorder is still unknown [4]. The relationship between sperm function and the composition of seminal plasma has been the focus of recent proteomics advancements [5–7]. Seminal plasma, which is primarily derived from the seminal vesicles (~ 65% of ejaculate volume) as well as the testes, epididymides, prostate, and vas deferens ampullae [8] Seminal plasma does not participate in spermatogenesis (a process confined to the testis), but provides the physical and metabolic environment necessary for post-ejaculatory sperm survival, motility maintenance, and fertilization competence in the female reproductive tract. It contains a variety of proteins that are closely associated with sperm function and provides the physical and metabolic environment necessary for sperm survival and motility. Additionally, it enhances the fertilization environment within the female reproductive tract [9]. Seminal-plasma proteins play an important part in reproduction [10]. Firstly, they protect and nourish sperm, providing energy and nutrients that are essential for motility and viability [11] and protecting sperm from hostile conditions such as acidity and immune attack [12]. Secondly, they influence sperm motility and navigation: proteins such as secreted phosphoprotein 1, fructose-bisphosphate aldolase, and malate dehydrogenase 1 modulate swimming patterns and velocity [13, 14], while calcium-binding proteins and fibronectin may act as chemotactic si (...truncated)