BSCL2 Deficiency Cause Male Infertility in mice by Impairing Histone Acetylation during Spermiogenesis

Background BSCL2 is primarily known for its role in lipid metabolism, yet its impact on male fertility through metabolic pathways remains incompletely understood. Methods We established a BSCL2 gene knockout mouse and cell models, and employed immunofluorescence, Western blot, spatial metabolomics, and single-cell RNA sequencing to investigate the biological functions of BSCL2 in spermatogenesis and male fertility. Results Our findings show that BSCL2 knockout male mice exhibit infertility accompanied by defects inlate-stage spermatogenesis defects. Further analysis revealed that impaired histone acetylation leads to incomplete histone replacement in sperm. This defect is attributable to BSCL2 gene deletion, which disrupts fatty acid β-oxidation and the citric acid cycle, thereby diminishing acetyl-CoA production and subsequently reducing the availability of acetylation substrates. Conclusions Our data underscore the critical role of BSCL2-mediated histone acetylation in sperm maturation process.