{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:04:13Z","timestamp":1784178253344,"version":"3.55.0"},"reference-count":26,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Research and Development Program of Xianyang","award":["L2024-ZDYF-ZDYF-SF-0043"],"award-info":[{"award-number":["L2024-ZDYF-ZDYF-SF-0043"]}]},{"name":"Qinchuangyuan Traditional Chinese Medicine Industry Innovation Cluster Project","award":["L2024-QCY-ZYYJJQ-X152"],"award-info":[{"award-number":["L2024-QCY-ZYYJJQ-X152"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hepatitis B virus (HBV) infection remains a major global health burden, with chronic infection leading to severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). HBV-encoded X protein (HBx) plays a critical role in viral replication and pathogenesis by modulating host cellular processes, including autophagy and lysosomal function. However, the molecular mechanisms by which HBx disrupts lysosomal biogenesis and autophagic degradation remain elusive. In this study, we show that HBx downregulates the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, which leading to impaired lysosomal acidification and autophagosome\u2013lysosome fusion. Mechanistically, HBx-mediated TFEB downregulation involves the CUL4A (Cullin 4A)\/CUL4B (Cullin 4B)-DDB1 (DNA damage-binding protein 1) E3 ubiquitin ligase complex and is dependent on the DDB1-interacting motif in HBx. HBx mutants defective in DDB1 binding (HBxR96E and HBx\u0394DBD) fail to downregulate TFEB or impair lysosomal function. Collectively, our findings identify a pathway by which HBx disrupts lysosomal function via CUL4A\/CUL4B\u2013DDB1-dependent TFEB downregulation, providing insights into HBV-associated liver pathogenesis and highlighting potential targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/cells15141259","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:55:21Z","timestamp":1783990521000},"page":"1259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HBx Downregulates TFEB via the CUL4A\/CUL4B\u2013DDB1 Axis to Disrupt Lysosomal Function in Hepatocellular Carcinoma Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Chunyan","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China"},{"name":"The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6282-7319","authenticated-orcid":false,"given":"Yuanping","family":"Han","sequence":"additional","affiliation":[{"name":"The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Yang","sequence":"additional","affiliation":[{"name":"The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610065, China"},{"name":"School of Pharmacy, Zunyi Medical University, Zunyi 563003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e362","DOI":"10.1016\/S1473-3099(24)00307-4","article-title":"WHO\u2019s 2024 global hepatitis report","volume":"24","author":"Burki","year":"2024","journal-title":"Lancet Infect. 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