Pkm, which encodes pyruvate kinase muscle isoforms, is crucial for glycolysis, the metabolic pathway converting glucose to pyruvate. Alternative splicing of Pkm pre-mRNA generates PKM1 and PKM2 isoforms, and the shift from PKM1 to PKM2 is linked to the Warburg effect, where cancer cells prefer aerobic glycolysis over oxidative phosphorylation [1,2,4].

In a genetic HCC mouse model, a surrogate mouse-specific antisense oligonucleotide (ASO) induced Pkm splice-switching from PKM2 to PKM1. This led to increased pyruvate-kinase activity, altered glucose metabolism, and inhibited tumorigenesis without observable toxicity, suggesting a potential ASO-based therapy for HCC [1]. In vascular smooth muscle cells (VSMCs), prohibitin 2 deficiency facilitated Pkm1/2 mRNA splicing from PKM1 to PKM2, enhanced glycolysis, and promoted post-injury VSMC proliferation and neointima formation. This indicates that regulating Pkm splicing can impact VSMC phenotype and vascular disease-related processes [3].

In conclusion, Pkm plays a vital role in glycolysis and metabolic regulation, and its alternative splicing is closely associated with cancer and vascular diseases. The use of mouse models, such as the genetic HCC mouse model and the carotid artery injury model in VSMCs, has provided valuable insights into the role of Pkm in these disease conditions, offering potential therapeutic directions for treating HCC and vascular diseases.