Our study substantially advances the field by resolving a critical gap in understanding HEY1 regulation. Building on evidence that HEY1 undergoes ubiquitination during liver CSC differentiation, we elucidate how USP28 governs HEY1 protein stability-revealing novel mechanistic insights into immune evasion. Furthermore, our results demonstrate compelling clinical relevance: targeting excessive HEY1 stability via USP28 inhibition combined with PD-1 blockade represents a promising therapeutic strategy against HCC and other HEY1-driven malignancies.