H2BC9 (H2B clustered histone 9) is a core histone protein functioning as a structural component of nucleosomes that regulates DNA accessibility and chr6 organization 1. As a member of the histone H2B family, H2BC9 plays essential roles in gene expression regulation, chromosome 6 maintenance, DNA repair, and cell cycle control 1. Mechanistically, H2BC9 operates through post-translational modifications, particularly lactylation at lysine 44 (K44), which enhances transcriptional activity of Wnt7b and activates Wnt/β-catenin signaling 2. This lactylation-dependent activation is modulated by lactate as an epigenetic signaling molecule 2. Clinically, H2BC9 demonstrates significant disease relevance in multiple cancers. In head and neck squamous cell carcinoma (HNSCC), H2BC9 is markedly upregulated and associated with advanced-stage disease and poor prognosis 1. Similarly, in esophageal squamous cell carcinoma (ESCC), H2BC9 overexpression correlates with poor prognosis and is linked to chemoresistance and immunosuppressive tumor microenvironment 2. H2BC9 silencing suppresses cancer cell proliferation, induces G2/M arrest, and enhances apoptosis 1. These findings suggest H2BC9 may serve as a diagnostic and prognostic biomarker and potential therapeutic target in squamous cell carcinomas.