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This study conducted horizontal genomic surveillance of MPXV in Shenzhen from 2023 to 2024 to characterize the phylogenetic structure, mutational patterns, and adaptive evolution of locally circulating strains. Phylogenetic analysis showed 95.2% of strains belonged to the dominant lineage C.1.1, with 4.8% in lineage E.3, forming three distinct genetic clusters that indicate multiple independent introductions and established local transmission chains. Whole-genome mutational analysis identified 146 single-nucleotide polymorphisms (SNPs), 81.5% of which carried APOBEC3-mediated mutation signatures (TC &gt; TT and GA &gt; AA), reflecting host-driven antiviral editing. Notably, dynamic changes in low-complexity regions (LCRs) were observed, implying potential roles in genome plasticity and adaptive evolution. Functional analysis revealed non-synonymous substitution biases in host-interacting proteins OPG064, OPG145, and OPG210, while replication protein OPG105 remained conserved. Structural modeling identified critical substitutions in OPG002 (S54F), OPG016 (R84K), and OPG036 (R48C) that may enhance immune evasion by modulating TNF-\u03b1 signaling, NKG2D engagement, and Type I interferon antagonism. These findings illuminate unique MPXV evolutionary dynamics in Shenzhen, emphasizing continuous genomic surveillance for non-endemic outbreak preparedness.<\/jats:p>","DOI":"10.3390\/v17091214","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T12:18:18Z","timestamp":1757074698000},"page":"1214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phylogenetic and Molecular Evolutionary Insights into Monkeypox Virus Circulation in Shenzhen, China, 2023\u20132024"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8449-2385","authenticated-orcid":false,"given":"Chuan","family":"Shi","sequence":"first","affiliation":[{"name":"School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangqing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingdong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifeng","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6069-5867","authenticated-orcid":false,"given":"Ziquan","family":"Lv","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Disease Control and Prevention, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7832-9338","authenticated-orcid":false,"given":"Wei","family":"Tan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianru","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiological Laboratory, Baoan District Center for Disease Control and Prevention, Shenzhen 518101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1159\/000322101","article-title":"Orthopox viruses: Infections in humans","volume":"37","author":"Pauli","year":"2010","journal-title":"Transfus. 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