{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T01:50:06Z","timestamp":1789091406219,"version":"build-2803163510"},"reference-count":110,"publisher":"Open Exploration Publishing","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/doi.org\/10.37349\/Open_Exploration_Crossmark_Policy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The purpose of this review was to provide a comprehensive review of the latest insights on the pathogenesis of uveal melanoma (UM) and its intracellular pathways. This article covers the epidemiology of UM, racial predispositions, cytogenetic and chromosomal alterations, gene mutations, key defective pathways, and their underlying mechanisms, as well as the application of hallmarks of cancer to UM. A key knowledge gap remains in identifying the most effective targeted therapy and determining the central pathway linking multiple signaling networks. UM is a malignant tumor arising from uveal melanocytes, predominantly affecting the choroid, with both genetic and epigenetic contributors. Key cytogenetic alterations include monosomy 3, chromosome 6p gain, chromosome 1p loss, and chromosome 8q gain. The most important UM-related signaling pathways are RAS\/MAPK, PI3K\/Akt\/mTOR, Hippo-YAP, retinoblastoma (Rb), and p53 pathways. In the RAS\/MAPK pathway, GNAQ\/GNA11 mutations occur which account for more than 80% of UM cases. The PI3K\/Akt\/mTOR pathway promotes cyclin D1 overexpression and MDM2 upregulation, leading to p53 pathway inhibition. GNAQ\/GNA11 mutations activate YAP via the Trio-RhoGTPase\/RhoA\/Rac1 signaling circuit in the Hippo-YAP pathway. Rb pathway dysregulation results from cyclin D1 overexpression or cyclin-dependent kinase inhibitor (CDKI) inactivation. In the p53 pathway, UM is characterized by p53 mutations, MDM2 overexpression, and Bcl-2 deregulation. Eventually, the ARF-MDM2 axis serves as a critical link between the RAS and p53 pathways. Hallmarks of cancer, such as evasion of growth suppression and self-sufficiency in growth signals, are also evident in UM. Genetic and epigenetic alterations, including NSB1, MDM2 and CCND1 amplification, and BAP1 mutations, play pivotal roles in UM pathobiology. Thus, UM exhibits a multifactorial pathology. By consolidating key mechanisms underlying UM pathogenesis, this review provides a comprehensive perspective on the involved pathways, offering insights that may facilitate the development of effective therapeutic strategies.<\/jats:p>","DOI":"10.37349\/etat.2025.1002306","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T06:16:06Z","timestamp":1743574566000},"update-policy":"https:\/\/doi.org\/10.37349\/open_exploration_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Exploring recent advances in signaling pathways and hallmarks of uveal melanoma: a comprehensive review"],"prefix":"10.37349","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8310-3635","authenticated-orcid":false,"given":"Majid","family":"Banimohammad","sequence":"first","affiliation":[{"name":"Physiology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1975-9855","authenticated-orcid":false,"given":"Parsa","family":"Khalafi","sequence":"additional","affiliation":[{"name":"Physiology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3567-6054","authenticated-orcid":false,"given":"Danial","family":"Gholamin","sequence":"additional","affiliation":[{"name":"Physiology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9221-3964","authenticated-orcid":false,"given":"Zahra","family":"Bangaleh","sequence":"additional","affiliation":[{"name":"Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8286-3736","authenticated-orcid":false,"given":"Nahid","family":"Akhtar","sequence":"additional","affiliation":[{"name":"School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1307-9840","authenticated-orcid":false,"given":"Abhishikt David","family":"Solomon","sequence":"additional","affiliation":[{"name":"Adams School of Dentistry, Oral and Craniofacial Biomedicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8130-1822","authenticated-orcid":false,"given":"Pranav Kumar","family":"Prabhakar","sequence":"additional","affiliation":[{"name":"School of Allied Medical Sciences, Lovely Professional University, Phagwara 144411, India; Parul Institute of Applied Sciences & Research and Development Cell, Parul University, Vadodara 391760, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1050-7880","authenticated-orcid":false,"given":"Samira","family":"Sanami","sequence":"additional","affiliation":[{"name":"Abnormal Uterine Bleeding Research Center, Semnan University of Medical Sciences, Semnan 3514799442, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7628-0457","authenticated-orcid":false,"given":"Ajit","family":"Prakash","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7868-456X","authenticated-orcid":false,"given":"Hamidreza","family":"Pazoki-Toroudi","sequence":"additional","affiliation":[{"name":"Physiology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran; Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"21850","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"Beasley AB, Chen FK, Isaacs TW, Gray ES. 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