Background: Glycochenodeoxycholate (GCDA) is one of the major human bile salts. Bile salts stimulate cell survival and proliferation through the mitogen-activated protein kinase, but the downstream signaling mechanism(s) remains enigmatic. Mcl-1 is an antiapoptotic molecule of the Bcl2 family that is extensively overexpressed in tumor tissues of patients with hepatocellular carcinoma (HCC). Results: Here we found that exposure of HepG2 cells to GCDA results in activation of ERK1 and ERK2 and phosphorylation of Mcl-1 in a PD98059 (MEK inhibitor)-sensitive manner. GCDA stimulates Mcl-1 phosphorylation in cells expressing WT but not T163A Mcl-1 mutant, indicating that GCDA-induced Mcl-1 phosphorylation occurs exclusively at the T163 site in its PEST region. GCDA-induced Mcl-1 phosphorylation at T163 enhances the half-life of Mcl-1. Treatment of HepG2 cells with GCDA facilitates Mcl-1 dissociation from Mule (a physiological Mcl-1 ubiquitin E3 ligase). Specific depletion of Mcl-1 from HepG2 cells by RNA interference increases sensitivity of HepG2 cells to chemotherapeutic drugs (i.e. cisplatin and irinotecan). In addition to activation of the ERK/Mcl-1 survival pathway, GCDA can also induce dose-dependent apurinic/apyrimidinic (AP) sites of DNA lesions, which may partially neutralize its survival activity. Conclusion: Our findings suggest that bile salt may function as a survival agonist and/or potential carcinogen in the development of HCC. Molecular approaches that inactivate Mcl-1 by blocking its T163 phosphorylation may represent new strategies for treatment of HCC.

Aims: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide, with a high mortality rate at advanced stages. In this study, we investigated the effect of niclosamide on cell growth and drug sensitivity in human HCC and elucidated the underlying mechanism.

Background: The global rise in obesity has led to an increasing burden of hepatocellular carcinoma (HCC) associated with high BMI, alongside viral hepatitis. This study evaluates the global burden of HCC due to high BMI, using the Global Burden of Disease (GBD) framework. Methods: Data from GBD 2021 were analyzed to compare age-standardized death rates (ASDR) and disability-adjusted life-years (ASR) of DALYs for high BMI-associated HCC from 1990 to 2021. The Estimated Annual Percentage Change (EAPC) was calculated using linear regression, and the Nordpred model was applied for projections from 2022 to 2040. Results: From 1990 to 2021, both ASDR and ASR of DALYs for high BMI-associated HCC showed significant increases. The burden was higher in males, older age groups (especially 80+), and regions with intermediate SDI values. Projections suggest that the global burden will continue rising until 2040 but at a slower rate, potentially stabilizing by then. Conclusion: The global burden of high BMI-associated HCC is increasing, especially in males and the elderly. Tailored prevention and treatment strategies are crucial to address regional trends and mitigate the growing disease burden.