Pyruvate kinase is a key regulator in hepatic glucose metabolism, encoded by the gene pyruvate kinase liver/red blood cells (PKLR). Systems biology-based approaches, including metabolic and gene co-expression networks analyses, as well as genome-wide association studies (GWAS), have led to the identification of PKLR as a pivotal gene influencing liver metabolism in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carci-noma (HCC). Here, we review the critical role of PKLR in MASLD and HCC progres-sion and examine the effects of PKLR modulation both in vitro and in vivo. We also discuss the development of therapeutic strategies for patients with MASLD and HCC by modulating PKLR, highlighting its promising future in a broader range of liver diseases.
Highlights
The pyruvate kinase liver/red blood cell (PKLR) gene critically regulates hepatic glucose and lipidmetabolism, driving met-abolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC) pathogenesis via altered glycolysis and lipid metabolism, and mitochondrial dysfunction. PKLR expression shows sex-specific effects, with higher expression levels in men linked to increased MASLD severity, highlighting the need for personalized approaches in managing metabolic diseases. Recent progress in developing PKLR inhibitors, including small molecules, holds promise for targeted treatments of MASLD and HCC, with preclinical studies demonstrating potential for re-ducing liver fat and improving metabolic profiles.
