胰腺癌细胞经历复杂的代谢重编程以维持其生存和增殖。p53在肿瘤细胞铁死亡中表现出双重作用。然而，野生型p53在促进胰腺癌细胞铁死亡中的精确作用和机制仍不清楚。本研究应用生物信息学工具，对临床组织样本数据库进行分析，观察到溶质载体家族35成员F2（SLC35F2）在胰腺癌组织中明显上调的表达。我们的临床调查表明，SLC35F表达的升高与不良生存结果相关。通过多组学分析，我们发现SLC35F2影响转录组，并抑制胰腺癌细胞的铁死亡。此外，我们的研究结果揭示了p53在介导SLC35F2介导的胰腺癌细胞铁死亡中的关键作用，无论是体外还是体内。SLC35F2通过促进TRIM59介导的p53降解来抑制铁死亡。进一步的机制研究表明，SLC35F2与TRIM59的E3泛素连接酶SYVN1之间进行竞争性相互作用，从而稳定TRIM59的表达，进而促进p53的降解。利用蛋白质三维结构分析和药物筛选，我们鉴定到盐酸伊立替康和苯丙胺替磺酸盐作为靶向SLC35F2的化合物，增强了咪唑酮厄拉甾（IKE）对野生型p53患者来源的异种移植模型的抗肿瘤效应。然而，在p53突变的异种移植模型中，盐酸伊立替康和苯丙胺替磺酸盐并不改变瘤异种移植模型对IKE诱导的铁死亡的敏感性。总之，我们的工作建立了一个新的机制，即SLC35F2-SYVN1-TRIM59轴通过抑制内源性p53来关键调节胰腺癌细胞的铁死亡。因此，SLC35F2成为治疗胰腺癌的有希望的治疗靶点。© 2023作者，独家授权给斯普林格自然有限公司。

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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.