TMX1 promotes the progression of hepatocellular carcinoma by inhibiting ferroptosis via stabilizing FABP5.

Thioredoxin-related transmembrane protein 1 (TMX1), a member of the thioredoxin-like family, upregulated in certain human malignancies and is implicated in tumorigenesis and progression. However, its biological functions in hepatocellular carcinoma (HCC) remain largely unexplored. Through bioinformatic analysis and validation with clinical samples, it was determined that TMX1 expression is elevated in HCC patients and is associated with poor survival outcomes. Knocking down TMX1 resulted in a marked reduction in cell proliferation both in vivo and in vitro, whereas overexpressing TMX1 increased cell proliferation. Mechanistically, TMX1 binds to Fatty Acid-Binding Protein 5 (FABP5), thereby competitively blocking the interaction between FABP5 and the E3 ubiquitin ligase neuronally expressed developmentally downregulated 4 (NEDD4), and preventing K48-associated ubiquitination degradation of FABP5, thereby enhances the inhibition of FABP5-mediated ferroptosis signaling pathways. Furthermore, in TMX1-overexpressing HuH-7 cells, FABP5 knockdown negated the effects of TMX1 overexpression, suggesting that FABP5 mediates TMX1's regulation of HCC cell proliferation. Consequently, this study elucidates the mechanisms by which TMX1 contributes to HCC development, suggesting that TMX1 may serve as a potential biomarker and therapeutic target in the context of HCC.