最近的研究表明，铁依赖性调控的细胞死亡形式——铁死亡，在肿瘤的起始和进展中可能发挥着重要作用。前列腺六跨膜表皮抗原3（STEAP3）是一个参与调节细胞内铁稳态的铁还原酶。然而，STEAP3在人类癌症中的临床意义和生物学功能尚不清楚。通过全面的生物信息学分析，我们发现STEAP3的mRNA和蛋白表达在GBM、LUAD和UCEC中上调，在LIHC中下调。生存分析表明，STEAP3仅在胶质母细胞瘤中具有预后意义。多因素Cox回归分析表明，高STEPA3表达与恶性预后有关。STEAP3表达显著与启动子甲基化水平呈负相关，甲基化水平较低的患者预后比甲基化水平较高的患者更差。单细胞功能状态图谱显示STEAP3调节GBM中的上皮-间质转化（EMT）。此外，创伤愈合和Transwell侵袭实验的结果表明，敲低STEAP3抑制了T98G和U251细胞的迁移和侵袭。功能富集分析表明，与STEAP3共表达的基因主要参与炎症和免疫相关通路。免疫学分析显示，STEAP3表达与免疫浸润细胞显著相关，包括巨噬细胞和中性粒细胞，尤其是M2型巨噬细胞。低STEAP3表达的个体比高STEAP3表达的个体更容易对免疫治疗做出反应。这些结果表明STEAP3促进了胶质瘤的进展，凸显了其在调节免疫微环境中的关键作用。© 2023 Deng et al.

Recent studies have suggested that ferroptosis, a form of iron-dependent regulated cell death, might play essential roles in tumor initiation and progression. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a ferrireductase involved in the regulation of intracellular iron homeostasis. However, the clinical significance and biological function of STEAP3 in human cancers remain poorly understood. Through a comprehensive bioinformatics analysis, we found that STEAP3 mRNA and protein expression were up-regulated in GBM, LUAD, and UCEC, and down-regulated in LIHC. Survival analysis indicated that STEAP3 had prognostic significance only in glioma. Multivariate Cox regression analysis revealed that high STEPA3 expression was correlated with poor prognosis. STEAP3 expression was significantly negatively correlated with promoter methylation level, and patients with lower STEAP3 methylation level had worse prognosis than those with higher STEAP3 methylation level. Single-cell functional state atlas showed that STEAP3 regulated epithelial-to-mesenchymal transition (EMT) in GBM. Furthermore, the results of wound healing and transwell invasion assays demonstrated that knocking down STEAP3 inhibited the migration and invasion of T98G and U251 cells. Functional enrichment analysis suggested that genes co-expressed with STEAP3 mainly participated in inflammation and immune-related pathways. Immunological analysis revealed that STEAP3 expression was significantly correlated with immune infiltration cells, including macrophages and neutrophils, especially the M2 macrophages. Individuals with low STEAP3 expression were more likely to respond to immunotherapy than those with high STEAP3 expression. These results suggest that STEAP3 promotes glioma progression and highlight its pivotal role in regulating immune microenvironment.© 2023 Deng et al.