Casein kinase 1 epsilon (CK1ε) as a potential therapeutic target in chronic liver disease

Abstract

Importance: Chronic liver disease (CLD) is a significant global health concern, often progressing to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma in both humans and animals. Despite substantial research efforts, effective CLD treatments remain scarce. Casein kinase 1 epsilon (CK1a), a serine/threonine kinase, plays a pivotal role in several critical signaling pathways, including the Wingless/Integrated (Wnt)/(3-catenin, HIPPO, and mitogen-activated protein kinase (MAPK) pathways, all of which contribute to liver disease progression. Observations: CK1a regulates key pathways that drive liver fibrosis, inflammation, and cancer. Its involvement in lipid metabolism and adipogenesis links CK1a to metabolic dysfunctional-associated steatotic liver disease. Elevated CK1a levels are observed in disease models beyond CLD, underscoring its broad role in pathological conditions. Moreover, CK1a phosphorylates critical proteins such as Wnt/(3-catenin, RAS/MAPK, phosphoinositide 3-kinase/protein kinase B, transcription coactivators yes-associated protein 1 and the PDZbinding motif, and Sprouty homolog 2, suggesting potential influence on liver cell function and fibrosis development. Preclinical models demonstrate that CK1a inhibitors, including PF-4800567, PF-670462, and IC261, effectively reduce tumor growth and fibrosis of variable etiologies. Conclusions and Relevance: CK1a's central role in liver disease progression makes it a compelling target for therapeutic strategies. Targeting CK1a with small molecules or gene therapies could offer novel treatment avenues for CLD. However, challenges related to target specificity and safety must be addressed. Further research and translational studies could pave the way for precision medicine approaches, enhancing treatment outcomes for both animals and humans with CLD.