Histone Lactylation-Driven GPD2 Mediates M2 Macrophage Polarization to Promote Malignant Transformation of Cervical Cancer Progression

Cervical cancer (CC) is the most common cancer in women. This study aims to explore the molecular mechanism of lactate secreted by CC cells modulating macrophage polarization in CC via histone lactylation. Normal cervical epithelium (NCE), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and cervical squamous cell carcinoma (CESC) were collected to assess H3K18la level and macrophage infiltration. Macrophages were incubated with SiHa cell-derived conditioned medium to detect M1 and M2 markers. NCE, HSIL, and CESC samples were used for ChIP-seq of H3K18la. Histone lactylation-dirven GPD2 was knocked down in macrophages. Compared to NCE, H3K18la level and M2 macrophage abundance were increased in LSIL, HSIL, and CESC. Lactate secreted by CC cells upregulated H3K18la and M2 markers but downregulated M1 markers in macrophages. ChIP-seq revealed that upregulated pathways in HSIL vs. NCE and CESC vs. HSIL were commonly enriched in lipid metabolism. Notably, lactate upregulated H3K18la-modified GPD2 expression in macrophages, and GPD2 knockdown reversed lactate induction to M2 macrophages. Collectively, lactate secreted by CC cells upregulates GPD2 via histone lactylation, thereby promoting M2 macrophage polarization in CC. This study provides new insights into the role of histone lactylation in macrophage polarization in the malignant transformation of CC.