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This review provides a comprehensive synthesis of the evolving Mpox threat, analyzing the dynamics of MPXV clades (I, Ia\/Ib, II, IIa\/IIb), with a focus on the enhanced transmissibility of the emergent Clade Ib variant linked to APOBEC3-mediated mutations. We detail the virus\u2019s genetic and structural characteristics, its unique cytoplasmic replication cycle, and sophisticated immune evasion strategies, including the interference with type I interferon signaling and modulation of pro-inflammatory cytokines. The review examines changing transmission paradigms, highlighting the role of sustained human-to-human and sexual transmission in recent outbreaks, and discusses the clinical spectrum of disease, from classic febrile rash to atypical presentations and severe outcomes in immunocompromised individuals. A significant portion of this analysis is dedicated to the profound implications for reproductive health, covering vertical transmission with high rates of fetal loss, viral persistence in semen, and potential impacts on fertility. We evaluate current diagnostic standards, such as PCR, alongside emerging techniques, and assess the efficacy of antiviral therapies, including tecovirimat, brincidofovir, and cidofovir. The status of vaccination, from second-generation (ACAM2000) to third-generation (MVA-BN and LC16m8) platforms, is critically appraised for its role in outbreak control. Furthermore, we explore the successes and hurdles of public health strategies, including surveillance, contact tracing, and community engagement, in managing stigma and ensuring equity. The review concludes by outlining future perspectives, emphasizing the urgent need for enhanced surveillance, accessible countermeasures, and research into broad-spectrum antivirals and vaccines to prepare for the ongoing threat of MPXV.<\/jats:p>","DOI":"10.3389\/fcimb.2025.1677762","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T07:29:58Z","timestamp":1770622198000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The evolving mpox threat (2022-2024): clade dynamics, immune evasion, and escalating global health challenges"],"prefix":"10.3389","volume":"15","author":[{"given":"Muhammad","family":"Irfan Khan","sequence":"first","affiliation":[{"name":"College of Animal Sciences and Technology, Yangzhou University","place":["Yangzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Saleh","sequence":"additional","affiliation":[{"name":"College of Animal Sciences and Technology, Yangzhou University","place":["Yangzhou, Jiangsu, China"]},{"name":"Animal and Fish Production Department, Faculty of Agriculture (Al-Shatby), Alexandria University","place":["Alexandria, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahmat","family":"Ali","sequence":"additional","affiliation":[{"name":"College of Animal Sciences and Technology, Yangzhou University","place":["Yangzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rifat Ullah","family":"Jan","sequence":"additional","affiliation":[{"name":"College of Animal Sciences and Technology, Yangzhou University","place":["Yangzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Gu","sequence":"additional","affiliation":[{"name":"College of Animal Sciences and Technology, Yangzhou University","place":["Yangzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Dejun","sequence":"additional","affiliation":[{"name":"College of Animal Sciences and Technology, Yangzhou University","place":["Yangzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1080\/21681805.2022.2138534","article-title":"Isolated monkeypox genital lesions","volume":"57","author":"Abou Chakra","year":"2023","journal-title":"Scand. 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