HNF4α-HKDC1 axis orchestrates a metabolic rewiring to promote migration and metastasis in advanced gastric cancer.

Metastatic gastric cancer (GC) has a poor prognosis. Recent research demonstrated the aberrant expression of nuclear receptor HNF4α and the regulatory roles of its isoforms during the processes of tumorigenesis and development. However, the expression patterns of HNF4α and its potential as a therapeutic target in metastatic GC remain elusive. In this study, we unveiled that P2 promoter-driven HNF4α (P2-HNF4α) was highly expressed in distant metastasis of GC, playing a pivotal role in fostering the migration and metastasis of GC cells both in vitro and in vivo. The transactivational activity was essential for HNF4α to promote GC cell migration. An integrative analysis of transcriptome and metabolome implied the involvement of the glycolytic pathway in the promotion of GC cell migration by P2-HNF4α. We further found that P2-HNF4α directly bound to the enhancer of the HKDC1 gene and upregulated its expression, thereby orchestrating a metabolic rewiring conducive to promoting GC migration and metastasis. Mycophenolic acid, an active metabolite of the FDA-approved drug mycophenolate mofetil, demonstrated the ability to suppress HKDC1 expression and GC migration and metastasis in vitro and in vivo through antagonizing HNF4α. Therefore, this study sheds light on the HNF4α-HKDC1 axis as a key player in GC metastasis, providing a promising targeted therapeutic strategy for metastatic GC.