铁死亡是一种以铁为依赖的细胞死亡过程，是肺鳞状细胞癌（LUSC）的潜在治疗策略。白藜芦醇（RES）是一种抗肿瘤多酚。然而，RES是否以及如何治疗LUSC还不确定。本研究旨在研究RES对LUSC的影响并探究其潜在机制。本研究采用蛋白质组学、生物信息学、临床样本和细胞实验相结合的方法研究HMMR与铁死亡信号通路之间的相互作用，探讨RES在调节肿瘤免疫微环境和CD8+T细胞的抗肿瘤作用方面的作用。铁死亡信号通路和HMMR参与了LUSC的肿瘤免疫微环境，并与LUSC患者的预后恶化相关。RES + H520细胞通过降低GPX4和SLC7A11的表达、诱导ACSL4和TFRC的表达，主要通过诱导更高水平的铁死亡和MDA实现。HMMR、GSH和SOD含量低于H520细胞。当HMMR表达时，SLC7A11也高表达在LUSC中，并且HMMR表达与SLC7A11之间存在相互作用。此外，RES增加了TNF-α、IFN-γ、IL-12和IL-2的表达，并增加了CD8+T细胞在LUSC中的细胞毒作用。白藜芦醇调节SLC7A11-HMMR相互作用，激活铁死亡，增强CD8+T细胞的细胞毒作用，调节肿瘤免疫微环境。基于LUSC的病理发生机制和RES的临床疗效，本研究探讨了RES对LUSC的影响，阐明了其生物学效应，并为RES的临床应用提供了细胞生物学依据。这将指导临床联合应用和个体化医疗，提高免疫治疗的应答率，使更多LUSC患者受益。版权所有©2023 Elsevier B.V.。保留所有权利。

Ferroptosis, an iron-dependent cell death process, is a potential therapeutic strategy for Lung squamous cell carcinoma (LUSC). Resveratrol (RES) is an anti-tumor polyphenol. However, whether and how RES treats LUSC is not yet known. This study aimed to investigate the effect of RES on LUSC and to explore its potential mechanism. This study used a combination of proteomics, bioinformatics, clinical samples, and cell experiments to study the interaction between HMMR and the ferroptosis signaling pathway and investigate the role of RES in regulating tumor immune microenvironment and anti-tumor by cytotoxic CD8 +T cells in LUSC. Ferroptosis signaling pathway and HMMR were involved in the LUSC tumor immune microenvironment and correlated with worse prognosis of LUSC patients. RES+H520 cells induced a higher level of ferroptosis and MDA, mainly by reducing the expression of GPX4 and SLC7A11, inducing the expression of ACSL4 and TFRC. HMMR, GSH, and SOD contents were lower observed than in H520 cells. When HMMR was expressed, SLC7A11 was also highly expressed in LUSC, and there was an interaction between HMMR expression and SLC7A11. In addition, RES increased the TNF-α, IFN-γ, IL-12, and IL-2 expression and increased the cytotoxic effects of CD8 +T cells expressions in LUSC. Resveratrol regulates SLC7A11-HMMR interaction, activates ferroptosis, enhances the cytotoxic effect of CD8 +T cells, and regulates the tumor immune microenvironment. Based on the pathogenesis of LUSC and the clinical efficacy of RES, this study explored the influence of RES on LUSC, clarified its biological effects, and further provided cell biological basis for the clinical application of RES, which could guide clinical combination and personalized medicine, improve the response rate of immunotherapy and benefit more patients with LUSC.Copyright © 2023 Elsevier B.V. All rights reserved.