Jenke Robert, Heinrich Theresa, Lordick Florian, Aigner Achim
Department of Medicine, Division of Oncology, University of Leipzig Medical Center, Comprehensive Cancer Center Central Germany (CCCG), Leipzig, Germany.
Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany.
Cell Death Discov. 2025 Aug 22;11(1):398. doi: 10.1038/s41420-025-02707-2.
Gastric cancer remains one of the most lethal malignancies worldwide, with high relapse rates and limited survival for patients with advanced disease. Despite advances in targeted therapies and immune checkpoint inhibition, intrinsic tumor heterogeneity poses challenges for effective treatment. The HER3 receptor (ERBB3) has emerged as an important player in cancer progression, contributing to aggressive tumor behavior and poor prognosis. Recent evidence indicates that activating ferroptosis-an iron-dependent, non-apoptotic form of cell death-offers a promising strategy to inhibit cancer growth. In gastric cancer, ferroptosis plays a crucial role, and promoting this process may open new avenues for therapeutic intervention. Ferroptosis is characterized by iron-mediated lipid peroxidation of cell membranes and is critically regulated by the cystine/glutamate antiporter system (SLC7A11) and glutathione peroxidase 4 (GPX4). Our study aimed to investigate the relationship between ERBB3 and ferroptosis in gastric cancer. We found that high ERBB3 expression correlated with resistance to ferroptosis-inducing agents, including GPX4 and SLC7A11 inhibitors, across multiple cell lines. Vice versa, ERBB3 inhibition with TX1-85-1 induced lipid peroxidation in gastric cancer cells, with effects most pronounced in cell lines expressing higher SLC7A11 levels. Knockdown of ERBB3 reproduced these effects, suggesting SLC7A11 as a predictive marker. Importantly, combined inhibition of ERBB3 and GPX4 significantly enhanced lipid peroxidation and cytotoxicity, while ERBB3 activation by co-treatment with the ERBB3 ligand heregulin reduced lipid peroxidation in cells with lower baseline SLC7A11 expression. Analysis of glutathione levels and SLC7A11 expression further supported the role of ERBB3 in modulating ferroptosis sensitivity. These findings identify ERBB3 as a critical regulator of ferroptosis and a promising target for enhancing ferroptosis-mediated cell death. Its inhibition in combination with ferroptosis inducers may thus represent a particularly promising and efficacious therapeutic strategy in gastric cancer.
胃癌仍然是全球最致命的恶性肿瘤之一，晚期疾病患者的复发率高且生存率有限。尽管靶向治疗和免疫检查点抑制取得了进展，但肿瘤内在的异质性给有效治疗带来了挑战。HER3受体（ERBB3）已成为癌症进展中的一个重要因素，导致肿瘤侵袭性生长和预后不良。最近的证据表明，激活铁死亡（一种铁依赖性、非凋亡性的细胞死亡形式）为抑制癌症生长提供了一种有前景的策略。在胃癌中，铁死亡起着关键作用，促进这一过程可能为治疗干预开辟新途径。铁死亡的特征是铁介导的细胞膜脂质过氧化，并且由胱氨酸/谷氨酸反向转运体系统（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）严格调控。我们的研究旨在探讨胃癌中ERBB3与铁死亡之间的关系。我们发现，在多个细胞系中，ERBB3高表达与对铁死亡诱导剂（包括GPX4和SLC7A11抑制剂）的抗性相关。反之，用TX1 - 85 - 1抑制ERBB3可诱导胃癌细胞中的脂质过氧化，在表达较高SLC7A11水平的细胞系中效果最为明显。敲低ERBB3重现了这些效应，提示SLC7A11作为一个预测标志物。重要的是，联合抑制ERBB3和GPX4可显著增强脂质过氧化和细胞毒性，而通过与ERBB3配体这里格列宁共同处理激活ERBB3可降低基线SLC7A11表达较低的细胞中的脂质过氧化。对谷胱甘肽水平和SLC7A11表达的分析进一步支持了ERBB3在调节铁死亡敏感性中的作用。这些发现确定ERBB3是铁死亡的关键调节因子，也是增强铁死亡介导的细胞死亡的一个有前景的靶点。因此，在胃癌中抑制ERBB3并联合铁死亡诱导剂可能代表一种特别有前景且有效的治疗策略。
