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Although the canonical HBV proteins are well\u2010studied, the pathological roles of HBV spliced variants and their encoded proteins are poorly understood. In this study, we investigate the cancer\u2010promoting potential of hepatitis B doubly spliced protein (HBDSP), encoded by the 2.2\u2009kb doubly spliced variant of HBV, and its underlying mechanism in hepatocellular carcinoma (HCC). In vitro functional assays demonstrated that HBDSP induces epithelial\u2010mesenchymal transition (EMT) and enhances migration and invasion in HepG2 and Huh7 cells. Mechanistically, cellular and molecular approaches revealed that HBDSP enhanced the nuclear translocation of SP1 and ETS1, thereby facilitating their binding to the yes\u2010associated protein (\n                    <jats:italic>YAP<\/jats:italic>\n                    ) promoter and activating\n                    <jats:italic>YAP<\/jats:italic>\n                    transcription. Inhibition of YAP using either the pharmacological inhibitor Verteporfin or\n                    <jats:italic>YAP<\/jats:italic>\n                    \u2010specific siRNA effectively abolished HBDSP\u2010induced malignant phenotypes, confirming the essential role of YAP in this process. Notably, these effects were consistently validated in both HBV\u2010replicating HepG2.2.15 cells and HBV\u2010infected HepG2\u2010NTCP cells, further reinforcing the pathological relevance of HBDSP in HBV\u2010driven hepatocarcinogenesis. Taken together, we identify HBDSP as a novel viral effector that facilitates EMT, migration, and invasion in hepatoma cells via transcriptional activation of\n                    <jats:italic>YAP<\/jats:italic>\n                    in an SP1\u2010 and ETS1\u2010dependent manner. These findings suggest that HBDSP\u2010mediated activation of YAP may play a role in HBV\u2010driven HCC progression and could be explored further as a potential therapeutic axis, particularly in contexts where spliced HBV variants are prevalent.\n                  <\/jats:p>","DOI":"10.1002\/jmv.71046","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:09:20Z","timestamp":1783606160000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatitis B Doubly Spliced Protein (HBDSP) Promotes Epithelial\u2010Mesenchymal Transition, Migration, and Invasion via SP1\/ETS1\u2010Dependent YAP Activation in Hepatoma Cells"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2920-4624","authenticated-orcid":false,"given":"Xiazhen","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Peng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Ping","sequence":"additional","affiliation":[{"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Shao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences Fujian Medical University Fuzhou 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