Rethinking carnitine palmitoyltransferase II and liver stem cells in metabolic dysfunction-associated fatty liver disease-related hepatocellular carcinoma.

Abstract

This article discusses a recent study by Wang et al that sheds light on the metabolic and immunological mechanisms driving the progression of metabolic dysfunction-associated fatty liver disease (MAFLD) to hepatocellular carcinoma (HCC). The study highlights the role of mitochondrial carnitine palmitoyltransferase II (CPT II) inactivity, which activates liver cancer stem cells marked by cluster of differentiation 44 (CD44) and CD24 expression, promoting HCC development. Using dynamic mouse models and clinical samples, Wang et al identified CPT II downregulation, mitochondrial membrane potential alterations, and reduced intrahepatic CD4⁺ T cell as key drivers of disease progression. The findings link these changes to steroid biosynthesis and p53 signaling, contributing to T-cell dysfunction and immunosuppression. This article emphasizes the relevance of these results in understanding MAFLD pathogenesis and discusses potential therapeutic strategies targeting CPT II activity, mitochondrial function, and immune surveillance to prevent or mitigate HCC development in advanced MAFLD.