The KAT2/HDACⅡa–PGK–ALDO axis constitutes a dual degradation inhibition cascade links energy stress to glycolytic amplification

Cells reprogram glycolysis pathway to cope with energy deficiency, in which the catalytic activity, stability, and noncanonical functions of glycolytic enzymes are finely regulated by posttranslational modifications (PTMs). Here, we report a metazoan-conserved dual degradation inhibition cascade whereby energy stress coordinates acetylation-phosphorylation crosstalk that simultaneously enhances glycolytic output and suppresses two protein degradation systems. Specifically, KAT2 (KAT2A)/HDACIIa (HDAC5)-mediated acetylation of PGK at K73 (PGK1; K75) antagonizes its ubiquitin–proteasomal degradation while strengthening its interaction with ALDO (ALDOA). Then, PGK exerts noncanonical kinase activity to phosphorylate ALDO at S272, thereby enhancing ALDO’s substrate affinity and suppressing its chaperone-mediated autophagic–lysosomal degradation by inhibiting the interaction with HSC70 to simultaneously stabilize and activate ALDO to amplify glycolytic flux. This ancient survival axis underlies thermotolerance divergence in oysters and is hijacked in human lung adenocarcinoma to drive malignant proliferation. Our study integrates environmental adaptation and tumorigenesis through a unified metabolic signaling axis, broadening our understanding of PTM crosstalk in evolution and disease.