SLC25A39 regulates Hedgehog signaling to promote tumor progression and sorafenib resistance in hepatocellular carcinoma

Abstract

Abstract Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), yet resistance limits its efficacy. The Hedgehog (HH) signaling pathway contributes to drug resistance by maintaining HCC stem cell characteristics, but its role at the single-cell level is underexplored. Utilizing single-cell RNA sequencing (scRNA-seq) and machine learning, we identified solute carrier family 25 member 39 (SLC25A39) as a key regulator of the HH pathway. Analyses of various cohorts revealed that elevated SLC25A39 correlates with poor prognosis in HCC patients. SLC25A39 knockdown inhibited cancer stem cell characteristics and reduced sorafenib resistance in vitro. Furthermore, combined SLC25A39 suppression and sorafenib treatment significantly hindered HCC progression in both in vitro and in vivo models. These findings highlight the potential of shSLC25A39 to enhance sorafenib sensitivity , presenting a new avenue for combating drug resistance and enhancing therapeutic effectiveness.