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It is necessary to explore valuable diagnostic markers and new therapeutic targets in HCC. Zinc finger protein 385A (ZNF385A) and zinc finger protein 346 (ZNF346) represent a unique class of RNA-binding Cys2 His2 (C2H2) zinc finger proteins that are involved in the regulation of cell cycle and apoptosis, but little is known of their roles in HCC. Based on multiple databases and analysis tools, we explored the expression, clinical relation, prognostic value, possible biological function, and pathways of ZNF385A and ZNF346, and their relationship with immune infiltration. Our results revealed that ZNF385A and ZNF346 were highly expressed and were associated with poor prognosis in HCC. Hepatitis B virus (HBV) infection may lead to the overexpression of ZNF385A and ZNF346, which was accompanied by elevated apoptosis and chronic inflammation. Moreover, ZNF385A and ZNF346 were positively correlated with immune-suppressive cells, inflammatory cytokines, immune checkpoint genes, and poor immunotherapy efficacy. Finally, the knockdown of ZNF385A and ZNF346 was observed to negatively affect the proliferation and migration of HepG2 cells in vitro. In conclusion, ZNF385A and ZNF346 are promising candidate biomarkers for the diagnosis, prognosis, and response to immunotherapy in HCC, and this study may help to understand the tumor microenvironment (TME) of liver cancer, and to develop new therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms24043155","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T03:34:30Z","timestamp":1675654470000},"page":"3155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["ZNF385A and ZNF346 Serve as Prognostic Biomarkers Associated with an Inflamed Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"24","author":[{"given":"Qihang","family":"Peng","sequence":"first","affiliation":[{"name":"College of Life Science, Yangtze University, Jingzhou 434025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6606-4005","authenticated-orcid":false,"given":"Jin","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Science, Yangtze University, Jingzhou 434025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Life Science, Yangtze University, Jingzhou 434025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Life Science, Yangtze University, Jingzhou 434025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongcui","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Life Science, Yangtze University, Jingzhou 434025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Deng","sequence":"additional","affiliation":[{"name":"College of Life Science, Yangtze University, Jingzhou 434025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Xiao","sequence":"additional","affiliation":[{"name":"College of Life Science, Yangtze University, Jingzhou 434025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Life Science and Healthy, Wuhan University of Science and Technology, Wuhan 430072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1032-280X","authenticated-orcid":false,"given":"Feng","family":"Ge","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-1579","authenticated-orcid":false,"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Life Science, Yangtze University, Jingzhou 434025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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