TXNIP restricts angiogenesis and atherosclerosis by targeting HK2 for mitophagic degradation to repress H3K9 lactylation

Pathological intraplaque angiogenesis is a critical determinant of plaque vulnerability and an important contributor to the residual cardiovascular risk that persists despite aggressive cholesterol-lowering therapies. However, the metabolic-epigenetic crosstalk driving this aberrant neovascularization remains poorly understood. We combined bioinformatics analyses with clinical atherosclerotic plaque specimen profiling and ApoE-knockout (ApoE KO ) mouse models to screen for differentially expressed endothelial factors. The identified molecule was further investigated through co-immunoprecipitation (Co-IP), LIR (LC3-interacting region) motif mutagenesis, mitophagy rescue assays using mitophagy inhibitor and activator, Seahorse metabolic flux analysis, and CUT&Tag to dissect the underlying mechanism. The in vivo relevance was evaluated in ApoE KO mice with TXNIP knockdown, with or without pharmacological hexokinase 2 (HK2) inhibition using 2-deoxyglucose (2DG). We identified thioredoxin-interacting protein (TXNIP) as a significantly downregulated protective factor in endothelial cells of unstable plaques. Mechanistically, TXNIP bound to LC3 via its conserved LIR motif and targeted mitochondria-associated HK2 for ubiquitin-independent mitophagic degradation. TXNIP deficiency removed this brake, leading to HK2 accumulation, enhanced aerobic glycolysis, and massive lactate production. The elevated lactate subsequently enriched histone H3 lysine 9 lactylation (H3K9la) at the promoters of pro-angiogenic genes, driving excessive endothelial proliferation and tube formation. In vivo, pharmacological inhibition of HK2 with 2DG effectively reversed pathological angiogenesis and improved plaque stability in TXNIP-knockdown ApoE KO mice. Our findings reveal a TXNIP-HK2-H3K9 lactylation axis that couples mitochondrial quality control and glycolytic reprogramming to epigenetic regulation. This axis represents a promising, non-cholesterol-dependent therapeutic target for stabilizing vulnerable atherosclerotic plaques.