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Chaperone\u2010mediated autophagy (CMA) contributes to HCV replication, but it remains unclear whether HCV regulates lysosome\u2010associated membrane protein 2\u2009A (LAMP\u20102A), the rate\u2010limiting receptor for CMA. Here, we examined LAMP\u20102A regulation in HCV\u2010infected Huh\u20107.5 cells. HCV infection increased LAMP\u20102A promoter activity, mRNA, and protein abundance, indicating transcriptional upregulation. Among candidate stress\u2010responsive transcription factors, nuclear factor erythroid 2\u2010related factor 2 (NRF2), hypoxia\u2010inducible factor 1\u03b1 (HIF\u20101\u03b1), and nuclear factor of activated T cells 1 (NFAT1) were elevated in infected cells. However, promoter mutagenesis identified NRF2 as the principal direct regulator. Mutation of the NRF2\u2010responsive antioxidant response element markedly reduced basal and HCV\u2010induced LAMP\u20102A promoter activity. Chromatin immunoprecipitation assays revealed NRF2 association with the LAMP\u20102A promoter, and HCV infection increased nuclear accumulation and Ser40 phosphorylation of NRF2. Functionally, shRNA\u2010mediated knockdown of LAMP\u20102A reduced intracellular HCV RNA and protein levels. These findings identify an NRF2\u2010LAMP\u20102A regulatory axis engaged during HCV infection and support a model in which HCV upregulates LAMP\u20102A to establish a cellular environment favorable for viral replication.<\/jats:p>","DOI":"10.1111\/1348-0421.70077","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T08:19:38Z","timestamp":1784535578000},"page":"462-473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatitis C Virus Enhances Lysosome\u2010Associated Membrane Protein 2\u2009A Transcription Through Nuclear Factor Erythroid 2\u2010Related Factor 2 to Support Viral Replication"],"prefix":"10.1111","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5391-3877","authenticated-orcid":false,"given":"Zihan","family":"Xu","sequence":"first","affiliation":[{"name":"Division of Infectious Disease Control, Center for Infectious Diseases Kobe University Graduate 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