胰腺癌是全球所有癌症类型中死亡率最高且预后最差的癌症之一。吉西他滨是胰腺癌常用的一线治疗药物；然而，在许多胰腺癌患者中观察到对吉西他滨治疗的耐药性迅速发展，这种现象限制了吉西他滨的生存益处。腺苷琥珀酸裂解酶 (ADSL) 是一种关键酶，在嘌呤从头生物合成中发挥双重功能，已被证明与各种癌症类型的临床侵袭性、预后和较差的患者生存率相关。在本研究中，我们观察到吉西他滨耐药细胞（PANC-1/GemR）中的ADSL水平显着低于亲本PANC-1细胞，并且ADSL的敲低显着增加了亲本PANC-1细胞的吉西他滨耐药性。我们进一步证明，ADSL 抑制 CARD 招募的膜相关蛋白 3 (Carma3) 的表达，从而导致吉西他滨耐药性增加，并且核因子红细胞 2 相关因子 2 (Nrf2) 调节亲本 PANC-1 细胞中的 ADSL 表达。这些结果表明，ADSL 是涉及吉西他滨耐药的胰腺癌的候选治疗靶点，并表明 Nrf2/ADSL/Carma3 通路对吉西他滨获得性耐药的胰腺癌具有治疗价值。© 2024 Wiley periodicals LLC。

Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.© 2024 Wiley Periodicals LLC.