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Histone lactylation is a novel epigenetic modification derived from lactate, but its role and mechanism in KRAS mutant colorectal cancer (CRC) progression remains to be fully elucidated. In this study, we first showed that mutant KRAS increased H3 lysine 9 lactylation (H3K9la) to promote CRC progression. We found that KRAS-mutant CRC tissues and cell lines exhibited higher lactylation and H3K9la levels compared to KRAS wild-type counterparts, driven by increased intracellular lactate. Elevated lactylation and H3K9la levels were associated with poor prognosis and advanced clinical stages. Inhibition of lactylation and H3K9la suppressed proliferation and migration of CRC cells. Mechanistically, mutant KRAS upregulated GRAMD1A expression by elevating H3K9la levels to increase chromatin accessibility. And increased GRAMD1A facilitated cholesterol metabolism to promote CRC growth and metastasis. Targeted inhibition of H3K9la or GRAMD1A reduced tumor growth in CRC patient-derived xenografts (PDX) models. Our study uncovered the critical role of H3K9la as a novel epigenetic modification in KRAS mutant CRC progression, suggesting H3K9la and its downstream gene GRAMD1A as promising targets for therapeutic intervention in KRAS mutant CRC and potential biomarkers for the prognosis of CRC patients.
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