吉西他滨是胰腺癌首选化疗药，但其耐药性显著降低疗效，探索其耐药分子机制具有十分重要的临床意义。我们发现吉西他滨增加 p37 AUF1的表达，进而抑制丝氨酸合成代谢关键酶3-磷酸甘油酸脱氢酶（PHGDH）经蛋白酶体降解。PHGDH抑制剂或 AUF1敲除可增加吉西他滨的敏感性，而铁死亡抑制剂明显消除这种增敏效应，提示p37 AUF1可能通过抑制细胞铁死亡促进吉西他滨耐药。进一步研究发现p37 AUF1可稳定OTUB1 mRNA而上调其表达，并且去泛素化酶OTUB1可与PHGDH结合。本项目拟深入解析p37 AUF1促进OTUB1表达的具体分子机制，明确OTUB1对PHGDH的去泛素化在p37 AUF1抑制细胞铁死亡和吉西他滨耐药中的作用。本项目的完成将阐明p37 AUF1/ OTUB1/PHGDH通路在胰腺癌对吉西他滨耐药中的关键作用及其分子机制，为胰腺癌的有效治疗提供新的潜在靶点。

Gemcitabine is the first-line treatment for pancreatic adenocarcinoma, but drug resistance significantly reduces its efficacy. So, it is of great significance to clarify the molecular mechanism of gemcitabine chemoresistance. We found that gemcitabine increased the expression of the p37 AUF1 isoform, thereby inhibiting proteasome-mediated degradation of 3-phosphoglycerate dehydrogenase (PHGDH), which is the key enzyme of serine anabolism. PHGDH inhibitors or Knockdown of AUF1 could sensitize pancreatic cancer cells to gemcitabine, while inhibitors of ferroptosis significantly eliminated this sensitization effect, suggesting that p37 AUF1 may promote gemcitabine resistance via inhibiting ferroptosis. We also found that p37 AUF1 could stabilize OTUB1 mRNA and upregulate its expression, and the deubiquitylase OTUB1could specifically bind to PHGDH. This project is intended to explore how p37 AUF1 upregulates the expression of OTUB1, clarify the involvement of OTUB1-mediated deubiquitination of PHGDH in ferroptosis and gemcitabine resistance. This project will clarify the key role of p37 AUF1/ OTUB1/PHGDH pathway in inhibition of ferroptosis and gemcitabine resistance, providing a potential target for chemotherapy of pancreatic cancer.