Targeting the H3K4me3-HNRNPC-CD24 Axis Overcomes Stemness and Immunosuppression in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is driven by cancer stemness and an immunosuppressive tumor microenvironment, which collectively contribute to therapeutic resistance. While the RNA-binding protein HNRNPC has been implicated in tumor progression, it has primarily been characterized as a downstream effector, and its autonomous regulatory functions, particularly in governing cancer stemness, remain entirely unexplored. Through multi-omics analyses of HCC cohorts, we identified HNRNPC as a pivotal driver of a high-risk molecular subtype. Mechanistically, HNRNPC expression was transcriptionally activated via WDR5/KMT2A complex-mediated deposition of H3K4me3 at its promoter. Functionally, HNRNPC was essential for maintaining cancer stemness, promoting tumor growth and metastasis, and conferring oxaliplatin resistance. Notably, depletion of HNRNPC reprogrammed the immunosuppressive microenvironment by enhancing CD8+ T cell infiltration, reducing T cell exhaustion, and polarizing macrophages toward an M1-like anti-tumor phenotype. At the molecular level, HNRNPC bound to the m6A-modified 3'UTR of CD24 mRNA in an RNP2 motif-dependent manner, thereby enhancing its stability and elevating CD24 protein expression. Therapeutically, we developed a novel lipid nanoparticle (LNP) encapsulating siRNA against HNRNPC. Systemically administered AP-EG-si potently suppressed tumor growth, attenuated stemness, and synergized with anti-PD-L1 therapy to enhance anti-tumor immunity. Our findings thus unveil the H3K4me3-HNRNPC-CD24 axis as a central epigenetic and post-transcriptional regulatory pathway that coordinately drives HCC stemness and immune evasion, nominating HNRNPC-targeted nanotherapy as a promising strategy for advanced HCC.