SLC35F2-SYVN1-TRIM59 Axis Critically Regulates Ferroptosis of Pancreatic Cancer Cells by Inhibiting Endogenous P53

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.