SFG enhances apoptosis of hepatocellular carcinoma by inhibiting tunneling nanotubes-mediated mitochondrial transport in the tumor microenvironment.

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, is characterized by a rising incidence and an alarmingly low rate of early diagnosis, presenting a significant global public health challenge. The development of safe and effective therapeutic agents for HCC is therefore a pressing necessity. Sophoraflavanone G (SFG), a bioactive flavonoid derived from Sophora flavescens Ait., has exhibited potent antitumor activity. However, its specific efficacy against HCC and the underlying molecular mechanisms remain poorly elucidated. In vitro studies have demonstrated that SFG suppresses HCC cell proliferation and migration in a dose-dependent manner, induces mitochondrial dysfunction, and activates intrinsic apoptotic pathways. Consistent with these results, in vivo experiments utilizing a HepG2 xenograft model confirmed that SFG, administered at doses ranging from 12.5 to 50 mg/kg, effectively inhibits tumor growth without causing observable toxicity. These findings further support the activation of mitochondrial-dependent apoptosis in response to SFG treatment. Importantly, SFG was also found to interfere with the unidirectional mitochondrial transfer mediated by tunneling nanotubes (TNTs) between cancer-associated fibroblasts (CAFs) and HCC cells. This disruption attenuated the pro-survival influence of the tumor microenvironment and enhanced apoptosis in HCC cells. In summary, this study provides the first evidence that SFG exerts potent anti-HCC effects through dual mechanisms: direct induction of mitochondrial apoptosis and indirect disruption of TNT-mediated stromal support. These findings highlight the therapeutic potential of SFG as a promising candidate for the treatment of HCC.