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This study investigates the lactylation (kla) modification of SPTAN1 (SPTAN1\u2010kla) and its mechanistic contributions to hepatitis B virus (HBV)\u2010related hepatocellular carcinoma (HCC). Results indicate that SPTAN1 undergoes lactylation at lysine residues K1952 and K1957 specifically in HBV\u2010positive HCC tissues. Alanyl\u2010tRNA synthetase 1 (AARS1) mediates SPTAN1\u2010kla formation, while histone deacetylase 1 (HDAC1) acts as a delactylase. HBV infection enhances lactate production by inducing the expression of HK2, promoting SPTAN1\u2010kla formation, and disrupting the liquid\u2010liquid phase separation (LLPS) of cytoplasmic SPTAN1, thereby facilitating its nuclear translocation. Within the nucleus, SPTAN1\u2010kla interacts with core\u2010binding factor \u03b2 (CBFB) to activate NOTCH1\/HES1 signaling, thereby promoting HCC cell proliferation. Furthermore, SPTAN1\u2010kla activates the COX2\/mPGES1 pathway through NOTCH1\/HES1 signaling, thereby enhancing the biosynthesis of prostaglandin E2 (PGE2) and increasing the infiltration of exhausted CD8\u207a T cells. Therapeutic targeting of SPTAN1\u2010kla using specific inhibitory peptides significantly attenuates HCC tumor growth in preclinical models. Our research identifies SPTAN1\u2010kla as a novel oncogenic driver in HBV\u2010related HCC, functioning via metabolic reprogramming and immune modulation. These findings position SPTAN1\u2010kla as a promising therapeutic target for developing precision interventions against HBV\u2010related HCC.<\/jats:p>","DOI":"10.1002\/advs.202507068","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T04:01:01Z","timestamp":1763352061000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Lactylated SPTAN1 Accelerates Hepatocellular Carcinoma Progression by Promoting NOTCH1\/HES1 Activation and Immunosuppression"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0793-1361","authenticated-orcid":false,"given":"Zengbin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Immunology School of Basic Medical Sciences Fujian Medical University  Fuzhou 350122 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Surgery Fujian Medical University Union Hospital  Fuzhou 350001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery Fujian Medical University Union Hospital  Fuzhou 350001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery Fujian Medical University Union Hospital  Fuzhou 350001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery Fujian Medical University Union Hospital  Fuzhou 350001 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