Salih Dian Jamel, Barsoom Saraa Hanna, Ahmed Ghazwan Fawzi, Hussien Shler Qasim, Al Ismaeel Qais, Alasady Asaad A B, Alsalim Tahseen A, Salih Ahmed Mohammed
Department of Medical and Surgical Sciences, University of Foggia, Via Dattoli, 42, 71121, Foggia, FG, Italy.
Department of Anatomy, Biology and Histology, College of Medicine, University of Duhok, Duhok, Iraq.
Saudi Pharm J. 2025 Jun 5;33(3):16. doi: 10.1007/s44446-025-00018-2.
Immune evasion in non-small cell lung cancer (NSCLC) is largely mediated by programmed death-ligand 1 (PD-L1), which is upregulated by interferon-gamma (IFN-γ)-induced STAT1 activation. Targeting this pathway may improve immunotherapy outcomes. Curcumin, a natural polyphenol, has been reported to modulate various oncogenic signaling pathways, but its role in inhibiting IFN-γ-driven PD-L1 expression in NSCLC remains unclear.
The NSCLC cell line A549 were treated with curcumin (50 µM) for 2 h before stimulation with IFN-γ (500 U/ml). Western blot, qRT-PCR, and immunofluorescence microscopy were used to evaluate STAT1 phosphorylation, PD-L1 expression, and the localization of phosphorylated STAT1 (p-STAT1). The expression of interferon-stimulated genes (ISGs), including SOCS1 and ISG15, was also examined. Additionally, the Resazurin assay was performed to assess cell viability.
IFN-γ significantly induced STAT1 phosphorylation, leading to a time-dependent upregulation of PD-L1 expression. Immunofluorescence confirmed that p-STAT1 is translocated to nucleus. Curcumin treatment inhibited STAT1 phosphorylation by 68% (p < 0.001), leading to a marked reduction in PD-L1 expression. Moreover, curcumin suppressed IFN-γ-induced SOCS1 (63%) and ISG15 (54%) expressions, indicating a broader effect on STAT1-mediated immune evasion. Finally, curcumin enhanced IFN-γ-mediated growth inhibition, reducing cell viability by 47% at 48 h (p < 0.01).
Curcumin effectively inhibits IFN-γ-induced STAT1 phosphorylation and PD-L1 expression, downregulates ISGs, and enhances IFN-γ-mediated tumor suppression. These findings suggest that curcumin may serve as a therapeutic adjuvant in NSCLC, potentially improving immune checkpoint inhibitor (ICI) efficacy.
非小细胞肺癌（NSCLC）中的免疫逃逸主要由程序性死亡配体1（PD-L1）介导，其通过干扰素-γ（IFN-γ）诱导的信号转导和转录激活因子1（STAT1）激活而上调。靶向该通路可能改善免疫治疗效果。姜黄素是一种天然多酚，据报道可调节多种致癌信号通路，但其在抑制NSCLC中IFN-γ驱动的PD-L1表达中的作用仍不清楚。
NSCLC细胞系A549在接受IFN-γ（500 U/ml）刺激前2小时用姜黄素（50 μM）处理。采用蛋白质免疫印迹法、定量逆转录聚合酶链反应（qRT-PCR）和免疫荧光显微镜评估STAT1磷酸化、PD-L1表达以及磷酸化STAT1（p-STAT1）的定位。还检测了包括细胞因子信号转导抑制因子1（SOCS1）和干扰素刺激基因15（ISG15）在内的干扰素刺激基因（ISGs）的表达。此外，进行刃天青试验以评估细胞活力。
IFN-γ显著诱导STAT1磷酸化，导致PD-L1表达呈时间依赖性上调。免疫荧光证实p-STAT1易位至细胞核。姜黄素处理使STAT1磷酸化降低68%（p < 0.001），导致PD-L1表达显著降低。此外，姜黄素抑制IFN-γ诱导的SOCS1（63%）和ISG15（54%）表达，表明其对STAT1介导的免疫逃逸具有更广泛的作用。最后，姜黄素增强IFN-γ介导的生长抑制作用，在48小时时使细胞活力降低47%（p < 0.01）。
姜黄素有效抑制IFN-γ诱导的STAT1磷酸化和PD-L1表达，下调ISGs，并增强IFN-γ介导的肿瘤抑制作用。这些发现表明姜黄素可能作为NSCLC中的治疗佐剂，潜在地提高免疫检查点抑制剂（ICI）的疗效。
