TEAD Inhibition as a Therapeutic Strategy for Chronic Liver Disease

Background: Chronic liver disease (CLD) affects approximately 1.5 billion people worldwide, with liver fibrosis, liver failure, and hepatocellular carcinoma (HCC) being major causes of mortality. Despite advances in understanding CLD, effective treatments to halt disease progression remain limited. ANLN/KIF23 and IHH, TEAD-targeting genes, are implicated in regulating HCC and metabolic dysfunction-associated steatotic liver disease (MASLD), the most common cause of CLD. We recently demonstrated that Rspo3 regulates liver homeostasis, including zonation and metabolism, highlighting its therapeutic potential.
Methods: We explored TEAD inhibition in CLD and HCC using tissue microarrays, HCC cell lines, and MASLD mouse models. TEAD gene signatures were identified through TEAD inhibitors and TEAD1-4 siRNA. TEAD inhibition was evaluated in a MASLD mouse model fed a CDA-HFD and an HCC mouse model.
Results: TAZ-TEAD pathway activation was observed in over 50% of HCC cases, regardless of etiology. A suppressed TEAD gene signature correlated with improved prognosis in TCGA-LIHC data. TEAD inhibition reduced cell proliferation and induced apoptosis in HCC cell lines. In MASLD and HCC models, TEAD inhibition reduced liver fibrosis, suppressed HCC progression, and upregulated Rspo3, improving reducing lipid accumulation and liver homeostasis.
Conclusion: TEAD inhibition may offer a novel therapeutic strategy for CLD and HCC by suppressing disease progression and promoting liver function recovery, presenting a promising target for future clinical development.