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Initially identified for their critical contributions to cerebellum development and neural patterning, ZIC genes have been found to influence a wide range of cellular processes. This review describes the structural attributes of ZIC genes, their biological functions during development, and their roles in cancer pathogenesis. Recent findings highlight the possibility of a dual nature of ZIC genes in oncogenesis, harboring oncogene or tumor suppressor activities depending on the cancer type and cellular context. We also explored the impact of epigenetic modifications and expression alterations of ZIC genes on tumor behavior, detailing their involvement in key oncogenic pathways including the sonic hedgehog, Wnt\/\u03b2-Catenin, TGF-\u03b2, PI3K\/AKT, and MAPK pathways. In conclusion, we aim to provide a better understanding of their complex roles in cancer, opening avenues for targeted therapeutic strategies and advancing diagnostic and prognostic evaluations across various cancers.<\/jats:p>","DOI":"10.1007\/s12672-025-03511-1","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T11:26:09Z","timestamp":1757935569000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The multifaceted roles of ZIC genes in cancer: from development regulators to cancer modulators"],"prefix":"10.1007","volume":"16","author":[{"given":"Dina","family":"Hesham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6465-9881","authenticated-orcid":false,"given":"Shahenda","family":"El-Naggar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"3511_CR1","doi-asserted-by":"publisher","unstructured":"Aruga J, et al. 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