Hyunsoo Rho

Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis. HK2 binds and sequesters glycogen synthase kinase 3 (GSK3) and acts as a scaffold forming a ternary complex with the regulatory subunit of protein kinase A (PRKAR1a) and GSK3β to facilitate GSK3β phosphorylation and inhibition by PKA. Thus, HK2 functions as an A-kinase anchoring protein (AKAP). Phosphorylation by GSK3β targets proteins for degradation. Consistently, HK2 increases the level and stability of GSK3 targets, MCL1, NRF2, and particularly SNAIL. In addition to GSK3 inhibition, HK2 kinase activity mediates SNAIL glycosylation, which prohibits its phosphorylation by GSK3. Finally, in mouse models of breast cancer metastasis, HK2 deficiency decreases SNAIL protein levels and inhibits SNAIL-mediated epithelial mesenchymal transition and metastasis.

Increased glycolysis, which leads to high lactate production, is a common feature of cancer cells. Recent evidence suggests that lactate plays a role in the post-translational modification of histone and nonhistone proteins via lactylation. In contrast to genetic mutations, lactylation in cancer cells is reversible. Thus, reversing lactylation can be exploited as a pharmacological intervention for various cancers. Here we discuss recent advances in histone and nonhistone lactylation in cancer, including L-, D- and S-lactylation, as well as alanyl-tRNA synthetase as a novel lactyltransferase. We also discuss potential approaches for targeting lactylation as a therapeutic opportunity in cancer treatment.

Steatotic liver diseases include metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease, and metabolic dysfunction and alcohol-related liver disease (MetALD), encompassing a spectrum of metabolic liver disorders that range from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Steatotic liver disease is primarily driven by alcohol consumption and metabolic dysfunction, making it the leading cause of chronic liver disease. Steatosis is defined by excessive fat accumulation in the liver without significant liver injury or inflammation. In contrast, inflammation is the predominant factor that drives the progression of steatosis to steatohepatitis and, ultimately, to cancer. In this review, we summarise the current understanding of the inflammatory mechanisms underlying the pathogenesis of MASLD and explore molecular targets that may offer the potential for pharmacological intervention. Additionally, given the pathological similarities between MASLD and MetALD, relevant inflammatory pathways in MetALD are briefly discussed to underscore both commonalities and key distinctions between the two conditions.