{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:26:23Z","timestamp":1792689983916,"version":"4.5.0"},"reference-count":87,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Phospholipase C zeta (PLC\u03b6) has emerged as a pivotal sperm-specific factor responsible for triggering oocyte activation, a process essential for successful fertilization and early embryogenesis. A narrative review was conducted to examine the molecular architecture and biochemical features of PLC\u03b6, with particular emphasis on how its distinctive structural domains facilitate the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and the induction of calcium (Ca2+) oscillations in the oocyte. Notably, PLC\u03b6 exhibits unique sensitivity to basal Ca2+ levels and the capacity to sustain repetitive intracellular Ca2+ transients that drive meiotic progression and block polyspermy. Clinically, PLC\u03b6 deficiency\u2014whether caused by genetic mutations, reduced expression, or improper localization\u2014represents a unifying explanation for certain forms of male infertility, including total fertilization failure (TFF) following intracytoplasmic sperm injection (ICSI). Globozoospermia is a prime example; this condition is characterized by round-headed sperm devoid of acrosomes and exhibiting significantly reduced or absent PLC\u03b6 and often results in fertilization failure. Diagnostic methods such as immunofluorescence, Western blotting, and the mouse oocyte-activation test collectively support the identification and characterization of PLC\u03b6-related defects, while genetic testing for mutations in the PLCZ1 gene has proven valuable for identifying hereditary causes of sperm-borne oocyte-activation deficiency (OAD). Therapeutic approaches range from assisted oocyte activation (AOA) with calcium ionophores to emerging interventions that introduce functional PLC\u03b6 protein or mRNA directly into the oocyte. These advancements demonstrate the rapid translation of foundational discoveries into clinically actionable interventions. Future investigations are poised to refine diagnostic assays, standardize measurement protocols, and explore the potential of gene therapy or CRISPR\/Cas9-mediated correction for heritable PLC\u03b6 abnormalities. By addressing both the molecular basis and translational applications of PLC\u03b6, recent findings underscore its indispensable role in fertility care and lay out a path toward further innovation in assisted reproductive technologies.<\/jats:p>","DOI":"10.3390\/medicina61060963","type":"journal-article","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T20:39:36Z","timestamp":1748205576000},"page":"963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phospholipase C\u03b6, the Molecular Spark of Fertilization and Male Infertility: Insights from Bench to Bedside"],"prefix":"10.3390","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4651-312X","authenticated-orcid":false,"given":"Aris","family":"Kaltsas","sequence":"first","affiliation":[{"name":"Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2141-4937","authenticated-orcid":false,"given":"Maria-Anna","family":"Kyrgiafini","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Comparative and Evolutionary Biology, Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6868-8927","authenticated-orcid":false,"given":"Zissis","family":"Mamuris","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Comparative and Evolutionary Biology, Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1198-9144","authenticated-orcid":false,"given":"Fotios","family":"Dimitriadis","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5287-4450","authenticated-orcid":false,"given":"Athanasios","family":"Zachariou","sequence":"additional","affiliation":[{"name":"Laboratory of Spermatology, Department of Urology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Chrisofos","sequence":"additional","affiliation":[{"name":"Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Sofikitis","sequence":"additional","affiliation":[{"name":"Laboratory of Spermatology, Department of Urology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/humupd\/dmv016","article-title":"Infertility around the globe: New thinking on gender, reproductive technologies and global movements in the 21st century","volume":"21","author":"Inhorn","year":"2015","journal-title":"Hum. 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