SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation
Cette étude met en évidence un mécanisme par lequel la sécernine SCRN1confère aux cellules du carcinome hépatocellulaire une résistance à la ferroptose en augmentant l'interaction entre la glutathion-peroxydase GPX4 et la phosphokinase STK38, laquelle phosphoryle GPX4 au niveau de la sérine 45
Systemic therapy is the optimal choice for individuals with unresectable or advanced hepatocellular carcinoma (HCC). However its effectiveness is constrained by resistance. Ferroptosis is a unique form of regulated cell death and plays an essential role in HCC systemic therapy. Here we identified that secernin-1 (SCRN1) was closely associated with ferroptosis resistance and poor prognosis in HCC. Specifically, high expression of SCRN1 enhances the interaction of phosphokinase serine/threonine kinase 38 (STK38) and glutathione peroxidase 4 (GPX4) to promote the phosphorylation of GPX4 at S45. This phosphorylation impairs heat shock protein family A member 8 (HSC70) recognition and degradation of GPX4 by chaperone-mediated autophagy, which further alleviates lipid peroxidation and ferroptosis. Our findings reveal a critical mechanism by which tumor cells antagonize ferroptosis through enhanced GPX4 phosphorylation and provide potential targets and strategies for HCC treatment.
Nature Cancer , résumé, 2025