Nuclear translocation of SLC25A10 isoform 3 promotes chemoresistance in HCC cells via CEBPB/BCL2A1 signaling.

SLC25A10, the mitochondrial dicarboxylate carrier, plays a crucial role in mitochondrial metabolism and protects against liver lipotoxicity. Moreover, its frequent amplification or mutation in cancers, particularly hepatocellular carcinoma (HCC), correlates with a poor prognosis. This study aimed to investigate the role of SLC25A10 in chemotherapy resistance in HCC and elucidate the underlying mechanisms. In this study, we found that hypoxia increased SLC25A10 expression with a preferential shift toward isoform 3 in HCC. This isoform interacts with the nuclear transporter IPO7 to translocate into the nucleus, where it binds to transcription factor CEBPB. This interaction upregulates the transcription of the anti-apoptotic gene BCL2A1, thereby enhancing HCC cell resistance to the chemotherapeutic agent, etoposide. Notably, disruption of the SLC25A10 isoform 3-IPO7 interaction significantly sensitized HCC tumors to etoposide in vivo, suggesting that targeting this interaction could be a promising therapeutic strategy to improve chemotherapy efficacy in HCC. This study reveals a novel nuclear function of the mitochondrial dicarboxylate carrier SLC25A10 in transcriptional regulation under hypoxic conditions, distinct from its canonical mitochondrial role. These findings expand our understanding of SLC25A10 biology and uncover a previously unrecognized mechanism that drives hypoxia-induced chemoresistance in HCC. Our findings suggest that SLC25A10 is a potential therapeutic target to overcome drug resistance in HCC.