Introduction: The final step of the fertilization process involves gametes adhesion and fusion. JUNO is an essential folate receptor 4 protein present in the ooplasm of oocytes, which binds to IZUMO1, its receptor on the sperm surface. Both proteins are indispensable for the sperm-oocyte interaction, and their absence results in infertility. Despite the importance of JUNO in reproduction, there is still controversy about how different factors affect the functionality of JUNO. Therefore, the goal of this study was to provide a comprehensive overview of what we know so far about the presence and functionality of JUNO. Methods: In order to accomplish this, a total of 198 articles were identified. Based on both inclusion and exclusion criteria, 40 articles were finally included in this study. Results: The results showed that during oocyte maturation, the expression levels of JUNO undergo alterations and, in some instances, cross-species gamete fusion is possible. Additionally, it has been observed that exposure of oocytes to factors such as bisphenol A, 17α-ethynylestradiol, diazinon, benzo(a)pyrene, butylparaben, bis(2-ethylhexyl) phthalate, hydroxyurea, dichlorophenol, isoniazid, and para-phenylenediamine disrupt JUNO and decrease the fertilization process rates. Moreover, exposure to ionic radiation, vitrification, and synthetic materials as microplastics has the same effect. Nonetheless, other compounds such as melatonin, mogroside V, cholesterol-loaded methyl-β-cyclodextrin, methyl-β-cyclodextrin, protocatechuic acid, coenzyme Q10, resveratrol, and Shoutai pills have been shown to enhance female fertility in terms of JUNO functionality. Conclusion: In summary, this update highlights the crucial role of JUNO during fertilization and reveals how different factors and experimental procedures affect its activity.

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