NADPH Oxidase 4 (NOX4), a member of the NOX family, has emerged as a significant source of reactive oxygen species, playing an important role in tumor cell proliferation, apoptosis, and other physiological processes. However, the potential function of NOX4 in gastric cancer (GC) cell proliferation is yet unknown. The aim of this study was to illustrate whether NOX4 plays a role in regulating gastric cancer cell growth. First, the clinical information from 90 patients was utilized to explore the clinical value of NOX4 as a predictive tool for tumor size and prognosis. Results showed that NOX4 expression was correlated with tumor size and prognosis. In vitro assays confirmed that knockdown of NOX4 expression blocked cell proliferation and the expression of Cyclin D1, BAX, and so on. Interestingly, NOX4 promoted cell proliferation via activation of the GLI1 pathway. GLI1, a well-known transcription factor in the Hedgehog signaling pathway, was overexpressed to test whether NOX4 activates downstream signaling via GLI1. Overexpression of GLI1 reversed the inhibition of proliferation induced by NOX4 knockdown. In addition, overexpression of NOX4 increased GLI1 expression, and depletion of GLI1 expression decreased the effects induced by NOX4 overexpression. Further, ROS generated by NOX4 was required for GLI1 expression, as shown by use of the ROS inhibitor, diphenylene iodonium (DPI). In summary, the findings indicate that NOX4 plays an important role in gastric cancer cell growth and apoptosis through the generation of ROS and subsequent activation of GLI1 signaling. Hence, the targeting of NOX4 may be an attractive therapeutic strategy for blocking gastric cancer cell proliferation.

NADPH氧化酶4（NOX4）是NOX家族的一员，已成为活性氧的重要来源，在肿瘤细胞的增殖，凋亡和其他生理过程中起着重要的作用。但是，NOX4在胃癌（GC）细胞增殖中的潜在功能尚不清楚。这项研究的目的是说明NOX4是否在调节胃癌细胞的生长中起作用。首先，利用来自90例患者的临床信息来探索NOX4的临床价值，将其作为预测肿瘤大小和预后的工具。结果表明，NOX4的表达与肿瘤的大小和预后相关。体外测定证实NOX4的敲低表达阻止细胞增殖以及细胞周期蛋白D1，BAX等的表达。有趣的是，NOX4通过激活GLI1途径促进细胞增殖。GLI1是Hedgehog信号通路中一个众所周知的转录因子，被过表达以测试NOX4是否通过GLI1激活下游信号传导。GLI1的过表达逆转了NOX4敲低诱导的增殖抑制。此外，NOX4的过表达增加了GLI1的表达，而GLI1的表达减少则降低了NOX4的过表达引起的效应。此外，NOX4产生的ROS如通过使用ROS抑制剂二亚苯基碘鎓（DPI）所显示的，GLI1的表达是必需的。总之，这些发现表明，NOX4通过产生ROS和随后激活GLI1信号传导在胃癌细胞的生长和凋亡中发挥重要作用。因此，靶向NOX4可能是阻断胃癌细胞增殖的有吸引力的治疗策略。