天然杀伤（NK）细胞在癌症免疫治疗领域越来越受关注。本研究旨在调查天然类黄酮化合物枸氨黄酮对永久性NK白血病细胞系KHYG-1抗侵袭性白血病细胞系K562的增加细胞毒性的影响。结果显示，枸氨黄酮通过诱导转录因子CREB的磷酸化，增加了KHYG-1细胞中细胞溶解分子穿孔素、疱状体A和B以及激肽激活物的表达，从而增加了对K562细胞的溶解。从机制上讲，我们发现枸氨黄酮可以增加t-Bid、剪切的半胱天冬酶3和剪切的PARP的表达，诱导K562细胞的凋亡。此外，枸氨黄酮通过减少SET和Ape1的表达来抑制DNA修复机制，导致非半胱天冬酶依赖的K562细胞死亡。在分子水平上，我们发现枸氨黄酮可以增加ERK、p38和JNK的磷酸化，从而增加KHYG-1细胞中疱状体B的表达。综上所述，本研究表明枸氨黄酮可以增加NK细胞对多种癌细胞的细胞毒性。 © 2023 Wiley Periodicals LLC.

Natural killer (NK) cells are gaining popularity in the field of cancer immunotherapy. The present study was designed to investigate the effect of a natural flavonol compound limocitrin in increasing cytotoxicity of a permanent NK leukemia cell line KHYG-1 against an aggressive leukemia cell line K562. The findings revealed that limocitrin increased the expressions of cytolytic molecules perforin, granzymes A and B, and granulysin in KHYG-1 cells by inducing phosphorylation of transcription factor CREB, leading to increased lysis of K562 cells. Mechanistically, limocitrin was found to increase the expressions of t-Bid, cleaved caspase 3, and cleaved PARP to induce K562 cell apoptosis. Moreover, limocitrin reduced the expressions of SET and Ape1 to inhibit DNA repair mechanism, leading to caspase-independent K562 cell death. At the molecular level, limocitrin was found to increase the phosphorylation of ERK, p38, and JNK to increase granzyme B expression in KHYG-1 cells. Taken together, the study indicates that limocitrin increases cytotoxicity of NK cells against a range of cancer cells.© 2023 Wiley Periodicals LLC.