SNAPIN Facilitates Progression of Hepatocellular Carcinoma by Hindering Ferroptosis Through KEAP1 Degradation Promotion.

Hepatocellular carcinoma (HCC) ranks among the most pervasive forms of cancer worldwide. In our study, we observed a notable overexpression of SNAPIN in human HCC tissues, which was linked closely to patient prognosis. Our experiments demonstrated that SNAPIN enhances the proliferative capacity of HCC cells. The knockdown of SNAPIN induces ferroptosis in HCC cells, whereas its overexpression partially resists the effects of ferroptosis inducers. As suggested by the above experimental findings, SNAPIN facilitates HCC progression by hindering HCC cell ferroptosis. Mechanistically, SNAPIN directly binds to KEAP1, facilitating its degradation via the autophago-lysosomal pathway, thereby undermining its stability. Consequently, NRF2 and its downstream target gene, GPX4, are upregulated. These alterations effectively mitigate lipid peroxidation damage, and ultimately impede HCC cell ferroptosis, potentially aiding in the progression of HCC. In conclusion, SNAPIN can negatively regulate the stability of KEAP1 protein, thereby initiating the NRF2/GPX4 pathway to hinder ferroptosis in HCC cells, ultimately facilitating HCC progression. Our results substantiate the pivotal function of SNAPIN in promoting HCC development, and this discovery is expected to provide an innovative therapeutic target for clinically managing HCC.