Li Xuan, Bai Ying, Zhou Jiawei, Cheng Anqi, Guo Jianqiang, Chen Maoqian, Hu Dong, Wu Jing
School of Medicine, Anhui University of Science and Technology, Huainan, 232000, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan, 232000, Anhui, China.
School of Medicine, Anhui University of Science and Technology, Huainan, 232000, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan, 232000, Anhui, China.
Eur J Pharmacol. 2025 Oct 5;1004:177984. doi: 10.1016/j.ejphar.2025.177984. Epub 2025 Jul 23.
Lung adenocarcinoma (LUAD), as a prevalent and life-threatening malignancy, poses a significant global health burden, particularly impacting patients and their families profoundly. Peroxiredoxin-2 (PRDX2) exhibits high expression levels in LUAD tissues. However, the identification of efficient and low-toxicity small-molecule inhibitors targeting PRDX2 from traditional Chinese medicine remains a challenging task. This study aims to identify potential inhibitors of PRDX2 in lung adenocarcinoma and elucidate their mechanism of action. Molecular docking and thermal shift assays were employed to evaluate the interaction between luteolin and PRDX2 protein. The effects of luteolin on lung cancer cell behavior were assessed through in vitro cellular experiments, and its efficacy on tumor growth was validated in a mouse model. Additionally, flow cytometry and Western blot analysis were utilized to investigate the mechanism of luteolin's action. Molecular docking and thermal shift experiments confirmed the binding affinity of luteolin to PRDX2. In vitro experiments demonstrated that luteolin significantly inhibits the proliferation and migration of LUAD cells. In vivo experiments showed that luteolin effectively suppresses tumor growth in an immunocompetent lung cancer mouse model. Western blot results untangled that luteolin promotes apoptosis of lung cancer cells by enhancing T-cell-mediated killing pathways via PRDX2. In summary, luteolin binds to PRDX2, inhibiting the JAK2/STAT3 pathway, suppressing PD-L1 expression, promoting the release of perforin and granzyme B from CD8 T cells, and inhibiting immune evasion in LUAD, thereby inhibiting the progression of lung adenocarcinoma.
肺腺癌（LUAD）作为一种常见且危及生命的恶性肿瘤，给全球健康带来了重大负担，尤其对患者及其家庭产生了深远影响。过氧化物酶2（PRDX2）在LUAD组织中呈现高表达水平。然而，从传统中药中鉴定出针对PRDX2的高效低毒小分子抑制剂仍然是一项具有挑战性的任务。本研究旨在鉴定肺腺癌中PRDX2的潜在抑制剂，并阐明其作用机制。采用分子对接和热位移分析来评估木犀草素与PRDX2蛋白之间的相互作用。通过体外细胞实验评估木犀草素对肺癌细胞行为的影响，并在小鼠模型中验证其对肿瘤生长的疗效。此外，利用流式细胞术和蛋白质免疫印迹分析来研究木犀草素的作用机制。分子对接和热位移实验证实了木犀草素与PRDX2的结合亲和力。体外实验表明，木犀草素显著抑制LUAD细胞的增殖和迁移。体内实验表明，木犀草素在具有免疫活性的肺癌小鼠模型中有效抑制肿瘤生长。蛋白质免疫印迹结果表明，木犀草素通过PRDX2增强T细胞介导的杀伤途径，促进肺癌细胞凋亡。综上所述，木犀草素与PRDX2结合，抑制JAK2/STAT3途径，抑制PD-L1表达，促进CD8 T细胞释放穿孔素和颗粒酶B，并抑制LUAD中的免疫逃逸，从而抑制肺腺癌的进展。
