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Here, we report that HEY1 plays a crucial role in sustaining HCC stemness and undergoes polyubiquitylation during liver CSC differentiation. Mechanistically, USP28 interacts with HEY1 and deubiquitinates its lysine 87 residue, thereby stabilizing HEY1 and enhancing the stem\u2010like properties of liver cancer cells. Moreover, IKK\u03b2 phosphorylates HEY1 at serine 40, facilitating its interaction with USP28. Loss of USP28 reduces PD\u2010L1 expression, increases effector cytokine production, and suppresses tumor growth in mice. Notably, combining a USP28 inhibitor with anti\u2010PD\u20101 immunotherapy results in enhanced tumor regression and significantly prolonged overall survival in mouse tumor models. Collectively, these findings identify USP28 as a potential biomarker for stratifying patients likely to benefit from anti\u2010PD\u20101\/PD\u2010L1 therapies in HCC. Furthermore, we uncover a previously unrecognized IKK\u03b2\u2010USP28\u2010HEY1 signaling axis that governs HEY1 stability and cancer stemness, offering new opportunities for synergistic therapeutic strategies in HCC.<\/jats:p>","DOI":"10.1002\/advs.75843","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T14:37:38Z","timestamp":1779806258000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["IKK\u03b2 and USP28 Regulate HEY1 Stability to Promote Cancer Stemness and Immune Evasion in Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Na","family":"Shao","sequence":"first","affiliation":[{"name":"Department of Pathology Xinqiao Hospital Third Military Medical University  Chongqing P. R. 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