The epigenetic KMT5C-HDAC1 axis promotes hepatocellular carcinoma stemness and progression through SERPINA4 repression and chromatin compaction.

Epigenetic dysregulation is a hallmark of hepatocellular carcinoma (HCC), yet the mechanisms linking chromatin modifiers to tumor stemness remain incompletely understood. Here, we identify the histone methyltransferase KMT5C as master regulator of HCC stemness and progression through integrative analyses of patient-derived organoids, murine models, and clinical cohorts. Mechanistically, KMT5C interacts with HDAC1 to promote H4K20me3-dependent chromatin compaction and histone deacetylation, cooperatively silencing tumor suppressor genes. Dual pharmacological inhibition of KMT5C and HDAC1 potently suppresses tumor growth, eliminates cancer stem cells, and sensitizes HCC to lenvatinib. Among their co-targets, we uncover SERPINA4 as a tumor suppressor that disrupts an oncogenic c-JUN/PRKCA/MAPK/c-FOS positive feedback loop. Notably, PRKCA is identified as a key and specific downstream effector of SERPINA4 in HCC. Clinically, KMT5C overexpression correlates with elevated PRKCA expression, reduced SERPINA4 levels, and poor patient survival. Our work establishes the KMT5C-HDAC1 axis as a central epigenetic switch that governs HCC stemness and progression, revealing a co-targeting strategy for the treatment of aggressive HCC.