DLX2 drives vascular calcification in chronic kidney disease through glycolytic activation: a mechanism epigenetically regulated by HDAC2.

Vascular calcification is a key pathological process contributing to cardiovascular mortality in chronic kidney disease (CKD). While HDAC2 is known to exert protective effects, its downstream mediators remain elusive. Here, we identify DLX2 as a critical pro-calcific driver and a target of HDAC2 in vascular smooth muscle cells (VSMCs). Transcriptomic analysis following HDAC2 overexpression revealed DLX2 as a key downregulated gene. Functional studies demonstrated that knockdown of DLX2 attenuated β-glycerophosphate (β-GP)-induced VSMC calcification, suppressed osteogenic transdifferentiation, and inhibited glycolysis in vitro. These protective effects were confirmed in a murine CKD model, where DLX2 knockdown alleviated aortic calcification and reduced glycolytic enzyme expression. Mechanistically, DLX2 was found to transcriptionally activate WNT1, promoting β-catenin nuclear translocation and driving a pro-glycolytic program. Furthermore, HDAC2 silenced DLX2 by reducing H3K9ac enrichment, thereby repressing its expression. Crucially, overexpression of DLX2 abolished the protective effect of HDAC2 against calcification. Our findings unveil DLX2 as an effector in uremic vascular calcification and glycolysis via the WNT1/β-catenin pathway, and establish the HDAC2-DLX2 axis as a promising therapeutic target for CKD.