HDAC8 Senses Lactate to Catalyze Reversible Lysine Lactylation Driving Oncogenic Transcription

AbstractMetabolites serve as direct conduits between cellular metabolism and epigenetic regulation. Lysine lactylation (Kla) is a recently identified modification derived from lactate, yet the enzymes responsible for its dynamic regulation, particularly within the nucleus, remain poorly defined. Here, we uncover an unconventional function for the class I deacetylase HDAC8 as a nuclear sensor and effector of lactate. Using chemical proteomics, we identify HDAC8 as a direct lactate-binding protein. Contrary to its canonical deacylase role, HDAC8 catalyzes reversible lysine lactylation in a lactate concentration-dependent manner. We demonstrate that HDAC8 lactylates both non-histone (e.g., ALDOA at K230/K322) and histone substrates, with a marked preference for H3K18. Mechanistically, HDAC8 undergoes auto-lactylation at K202, a modification essential for its lactyltransferase activity. Genomic profiling (CUT&Tag) reveals that HDAC8 shapes the H3K18la landscape, promoting its occupancy at gene promoters and driving the transcription of oncogenic pathways. Phenotypically, HDAC8 overexpression enhances hepatocellular carcinoma cell proliferation, which is abrogated by a lactylation-deficient mutant or an HDAC8 inhibitor. Our study redefines HDAC8 as a dual-function enzyme integrating lactate abundance into the epigenetic code through reversible Kla catalysis, revealing a novel metabolic-epigenetic axis in tumorigenesis.