Tenuigenin regulates succinylation via SIRT5 for suppressing the tumourigenicity of hepatocellular carcinoma cells

Tenuigenin (TEN) is an active component extracted from the Polygala tenuifolia root and has been reported to show anti-insomnia, anti- amnesia, neuroprotective, and anti-inflammatory effects. This study aimed to investigate the anti-tumour effects of TEN on hepatocellular carcinoma (HCC) cells and to explore any underlying molecular mechanisms. The findings demonstrated that TEN has strong anti-tumour effects in vivo and in vitro. Furthermore, TEN significantly inhibited HCC cell proliferation by inhibiting S-phase cell cycle entry, in addition to migration and the promotion of apoptosis in Hep3B and HCCLM3 cells. In vivo, TEN significantly suppressed tumour growth by decreasing Ki67 and BCL2 expression. Mechanistic exploration found that interference with central carbon metabolism via succinate metabolite synthesis inhibition was a mediator of these changes within HCC cells, suggesting that cancer cell metabolic pathways were affected by TEN treatment. In addition, TEN significantly increased the expression of desuccinylase-SIRT5, leading to reduced global succinylation and specific histone H3 lysine 122 succinylation (H3K122su), while simultaneously modulating the ERK/JNK signaling pathway in HCC cells. These findings demonstrated that TEN exerts its anti-tumor effect in HCC cells by targeting SIRT5-succinylation. Therefore, TEN is a strong potential candidate anti-tumour drug for targeted HCC treatment.