@Article{or.2026.083840,
AUTHOR = {Ganxin Wang, Zhongan Liu, Tian Zhou, Boting Yang, Jiaqin Chen, Jing Chen, Kai Huang, Yunqing Xu, Quan Tang, Xiangqian Yin, Guangqin Xiao, Sijia Zhang},
TITLE = {GPX4 Defines an Immune-Cold Phenotype and Poor Prognosis in Resected Lung Adenocarcinoma},
JOURNAL = {Oncology Research},
VOLUME = {34},
YEAR = {2026},
NUMBER = {8},
PAGES = {0--0},
URL = {http://www.techscience.com/or/v34n8/68050},
ISSN = {1555-3906},
ABSTRACT = {<b>Objectives:</b> Ferroptosis resistance may contribute to tumor progression and immune escape. This study evaluated the prognostic and immunological significance of glutathione peroxidase 4 (GPX4), a core ferroptosis-suppressive enzyme, in surgically resected lung adenocarcinoma. <b>Methods:</b> We retrospectively analyzed 104 patients with primary lung adenocarcinoma who underwent curative resection. GPX4 protein expression was assessed by immunohistochemistry (IHC) using the histological score (H-score), and patients were classified as GPX4-low (n = 54) or GPX4-high (n = 50). Intratumoral immune contexture was quantified using CD3, CD4, CD8, CD68, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) staining. Disease-free survival (DFS) and overall survival (OS) were analyzed using Cox regression. Cutoff sensitivity analyses, category consolidation, ridge-penalized Cox regression, events-per-variable assessment, bootstrap internal validation, and interobserver reproducibility testing were performed to strengthen statistical robustness. <b>Results:</b> GPX4-high tumors were associated with systemic inflammatory and immune-related features, including elevated fibrinogen (<i>p</i> = 0.015), lower lymphocyte-to-monocyte ratio (<i>p</i> = 0.003), and altered aspartate aminotransferase-to-alanine aminotransferase ratio (<i>p</i> = 0.028). GPX4-high tumors showed reduced intratumoral CD3<sup>+</sup>, CD4<sup>+</sup>, CD8<sup>+</sup>, and CD68<sup>+</sup> immune-cell infiltration, together with increased PD-1 and PD-L1 expression, indicating an immune-cold yet checkpoint-enriched phenotype. After category consolidation and ridge-penalized multivariable adjustment, high GPX4 expression remained independently associated with worse DFS (HR, 8.63; 95% CI, 2.99–24.91; <i>p</i> < 0.001) and OS (HR, 6.94; 95% CI, 2.44–19.74; <i>p</i> < 0.001). GPX4-based prognostic models showed bias-corrected C-index values of 0.782 for DFS and 0.826 for OS, with calibration slopes of 0.964 and 0.937, respectively. <b>Conclusions:</b> High GPX4 expression identifies a clinically adverse, ferroptosis-resistant, immune-remodeled phenotype in resected lung adenocarcinoma. Integrating GPX4 with clinicopathological and inflammatory variables may improve postoperative risk stratification.},
DOI = {10.32604/or.2026.083840}
}