Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition

作者：Chengyu Li, Chen Fu, Wenhan Zhou, Hongmin Li, Zhaojun Liu, Gang Wu, Tong He, Ming Shen, H. Liu · 发表于：Cell Communication and Signaling · 年份：2025 · DOI：10.1186/s12964-025-02366-x · 被引用次数：29 · 研究领域：Cancer, Hypoxia, and Metabolism、Metabolism, Diabetes, and Cancer、Mitochondrial Function and Pathology

Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia. Although prolyl hydroxylation-mediated degradation via the von Hippel-Lindau (VHL) ubiquitination complex is a well-established regulatory mechanism, the role of lactate-induced posttranslational modifications in HIF-1α stabilization remains incompletely understood. Here, we demonstrate that lactate induces lysine lactylation of HIF-1α at distinct residues across species-specifically, K644 in mice and K12 in humans and pigs-to increase protein stability by impairing VHL recognition. Mass spectrometry and mutagenesis analyses revealed that lactylation at these sites reduces K48-linked ubiquitination and proteasomal degradation, even when HIF-1α is hydroxylated. Structural modeling and functional assays revealed that lactylation sterically hinders VHL binding without affecting hydroxylation. Notably, lactylated HIF-1α exhibited increased transcriptional activity, as evidenced by increased promoter occupancy and upregulation of hypoxia-responsive genes (Vegfa, Glut1). Cross-species comparisons highlighted evolutionary divergence in lactylation sites while preserving the functional conservation of this modification. Our findings reveal that lactylation is a universal regulatory mechanism that overrides classical hydroxylation-dependent degradation, expanding our understanding of metabolic control over hypoxic signaling.