Coordination of SLC39A1 and DRP1 facilitates HCC recurrence by impairing mitochondrial quality control

Despite rapid advances in HCC therapy, surgical resection is still the most effective treatment. However, postoperative relapse develops in a large population and the mechanism remains to be explored.

HCC resection samples were retrospectively collected from 12 nonrelapsed and 15 relapsed HCC patients for RNA sequencing. Liver-specific solute carrier family 39 member 1 (SLC39A1) knockout mice were generated by crossing Alb-Cre mice and SLC39A1^flox/flox mice. Liver samples were examined for inflammation, fibrosis, proliferation, and apoptosis. Mitochondrial mass, autophagy, ROS, and mitochondrial membrane potential (MMP), were detected. Co-immunoprecipitation and molecular docking were used to identify protein interactions.

SLC39A1 is highly expressed in relapsed HCC patients and negatively correlated with overall survival. Knockdown of SLC39A1 inhibited cell proliferation by arresting the cell cycle and promoted cell apoptosis, accompanied by suppressing autophagic flux. Mechanistically, SLC39A1 interacts with a member of the dynamin superfamily of GTPases dynamin-related protein 1 (DRP1), followed by facilitating mitochondrial fission and MMP reduction. Inhibition of DRP1 abolished SLC39A1-induced mitochondrial division and MMP depolarization, while overexpression of DRP1 reversed mitochondrial fusion and MMP hyperpolarization in SLC39A1 silenced cells, accompanied by recuperative cell proliferative ability. SLC39A1^flox/flox,Alb-Cre mice displayed fewer tumour numbers and less liver damage compared with SLC39A1^flox/flox mice. A specific peptide targeting SLC39A1 to disturb the combination of full-length SLC39A1 and DRP1 efficiently suppressed HCC progression.

Our findings reveal a key role of SLC39A1-DRP1 interaction in HCC progression by disturbing mitochondrial quality control and providing a competitive peptide as a potential anti-tumour therapy.

SLC39A1 correlates with HCC recurrence and HCC mortality. Interaction of SLC39A1 and DRP1 facilitates HCC by regulating mitochondrial quality control. Specific peptide targeting SLC39A1 efficiently prevents HCC progression.