吉西他滨被视为胰腺癌的标准治疗方法，但药物耐药性的发展极大限制了化疗的有效性并增加了复发率。赖氧乙氧基2（LOXL2）在胰腺癌中高表达，并参与了癌变和EMT调节。然而，关于LOXL2在药物耐药性中的作用的研究有限。在这里，我们调查了LOXL2诱导机制以及LOXL2对吉西他滨耐药胰腺癌中EMT和CSC的影响。吉西他滨耐药胰腺癌细胞中激活了葡萄糖代谢，并相应地调节了NF-κB信号。活化的NF-κB通过与LOXL2和ZEB1的启动子结合直接诱导转录。ZEB1和LOXL2的共调控显著抑制了EMT过程。此外，通过调节MAPK信号活性，LOXL2的抑制减少了癌细胞干性标记物和干性的表达。LOXL2抑制剂抑制了吉西他滨耐药胰腺癌细胞的肿瘤生长，并提高了小鼠模型对吉西他滨的敏感性。关键信息：我们确定了一种特定的机制，用于诱导吉西他滨耐药胰腺癌中LOXL2过表达。综合以上结果，我们的研究结果表明LOXL2在维持吉西他滨耐药性中具有重要的调控作用，并且可能是治疗胰腺癌的有效靶点。© 2023. 作者。

Gemcitabine is considered a standard treatment for pancreatic cancer, but developing drug resistance greatly limits the effectiveness of chemotherapy and increases the rate of recurrence. Lysyl oxide-like 2 (LOXL2) is highly expressed in pancreatic cancer and is involved in carcinogenesis and EMT regulation. However, studies on the role of LOXL2 in drug resistance are limited. Here, we investigated the mechanism of LOXL2 induction and the effect of LOXL2 on EMT and CSC in gemcitabine-resistant pancreatic cancer. Glucose metabolism was activated in gemcitabine-resistant pancreatic cancer cells, and NF-κB signaling was regulated accordingly. Activated NF-κB directly induces transcription by binding to the promoters of LOXL2 and ZEB1. The EMT process was significantly inhibited by the coregulation of ZEB1 and LOXL2. In addition, LOXL2 inhibition reduced the expression of cancer stemness markers and stemness by regulating MAPK signaling activity. LOXL2 inhibits tumor growth of gemcitabine-resistant pancreatic cancer cells and increases the sensitivity to gemcitabine in mouse models. KEY MESSAGES: We identified a specific mechanism for inducing LOXL2 overexpression in gemcitabine-resistant pancreatic cancer. Taken together, our results suggest LOXL2 has an important regulatory role in maintaining gemcitabine resistance and may be an effective therapeutic target to treat pancreatic cancer.© 2023. The Author(s).