PKM2 AP: a micropeptide inhibits vascular calcification via molecular glue-mediated ubiquitination of PKM2.

Chronic kidney disease (CKD) is a major global public health challenge, and cardiovascular complications such as vascular calcification (VC) are crucial in CKD-related mortality. Emerging evidence shows that open reading frames (ORFs) within non-coding genomic regions can encode micropeptides, but their roles in VC progression remain largely unexplored. In this study, we identify a 40-amino acid micropeptide, termed PKM2 AP, encoded by an ORF2-containing intron-retaining transcript derived from the LINC01139 locus. PKM2 AP localizes to both mitochondrial and cytoplasmic compartments and interacts with pyruvate kinase M2 (PKM2), thereby promoting its ubiquitination-dependent degradation. Mechanistically, PKM2 AP functions as a molecular glue that facilitates the recruitment of the E3 ubiquitin ligase STUB1 to PKM2, leading to stabilization of the PKM2-PKM2 AP-STUB1 ternary complex and enhanced PKM2 degradation. Functionally, PKM2 AP-mediated PKM2 degradation suppresses aerobic glycolysis and lactate production, thereby attenuating osteogenic transition and VC progression. In vivo administration of PKM2 AP and genetic knock-in of ORF2 both alleviate vascular calcification phenotypes in mouse models. Collectively, our findings identify a VC-associated micropeptide functioning through a molecular glue-like mechanism and provide a potential therapeutic strategy for vascular calcification.