A positive feedback loop between TKT and c-Myc drives TACE resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) often receives transarterial chemoembolization (TACE), yet clinical benefit is limited by resistance driven by ischemia-induced adaptations. This study explains how transketolase (TKT) in the pentose phosphate pathway (PPP) modulates HCC progression and TACE refractoriness, and clarifies its mechanistic connection to oncogenic signaling. We integrated transcriptomic screening with analyses of TACE patient specimens, and performed gain and loss of function experiments across HCC cell lines. Functional assays, RNA-seq with pathway enrichment, western blotting, immunofluorescence, cycloheximide-chase and ubiquitination assays, and an orthotopic VX2 rabbit TACE model with imaging and immunohistochemistry were used. TKT emerged as a hub gene, was elevated in TACE-resistant patients, and promoted proliferation, migration, invasion, epithelial-mesenchymal transition, and apoptosis resistance. Mechanistically, TKT associates with RAF1, promoting phosphorylation of c-Raf at Ser338 and subsequent ERK activation, and stabilizes c-Myc by enhancing Ser62 phosphorylation and reducing ubiquitin-mediated degradation. Additionally, c-Myc enhances the transcriptional expression of TKT, creating a positive feedback loop between TKT and c-Myc. These findings identify a TKT/c-Myc positive feedback loop that underlies TACE resistance and HCC progression, nominating TKT as a biomarker of refractoriness and a therapeutic target to improve locoregional treatment outcomes.