Qiu Yi, Su Yuyuan, Sai Wenli, Feng Guijuan
Nantong University Medical College, Nantong, 226001, China.
Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, West Temple Rd.20, Nantong, 226001, China.
J Mol Histol. 2025 Mar 17;56(2):109. doi: 10.1007/s10735-025-10381-y.
Ferroptosis, a regulated iron-dependent cell death pathway driven by lipid peroxidation and mitochondrial dysfunction, has emerged as a critical player in diseases characterized by dysregulated iron metabolism and redox imbalance. In recent years, its therapeutic potential has garnered significant attention in head and neck squamous cell carcinoma (HNSCC), a malignancy notorious for its high incidence, frequent recurrence, and poor prognosis. This review systematically delineates the molecular underpinnings of ferroptosis in HNSCC pathogenesis and therapy, focusing on four interconnected axes: (1) iron homeostasis disruption, exemplified by dysregulation of the iron efflux channel ferroportin (FPN); (2) lipid peroxidation dynamics, mediated through key regulators such as SLC7A11; (3) mitochondrial remodeling, including structural and functional alterations during ferroptosis execution; and (4) critical signaling cascades, notably the PI3K-AKT-mTOR pathway, which orchestrates cellular survival and death decisions. Therapeutic exploration has identified ferroptosis inducers (e.g., erastin) as promising agents to disrupt redox equilibrium in HNSCC cells, while pharmacological inhibitors offer potential for mitigating off-target toxicity. Notably, combination strategies integrating ferroptosis modulation with conventional therapies or other programmed cell death mechanisms demonstrate synergistic efficacy, highlighting a paradigm shift in precision oncology. This study aims to provide a mechanistic framework for ferroptosis in HNSCC, bridging preclinical insights with translational opportunities. By elucidating context-dependent regulatory networks and optimizing therapeutic targeting, we propose novel strategies to overcome treatment resistance, ultimately improving clinical outcomes and quality of life for HNSCC patients.
铁死亡是一种由脂质过氧化和线粒体功能障碍驱动的受调控的铁依赖性细胞死亡途径，已成为以铁代谢失调和氧化还原失衡为特征的疾病中的关键因素。近年来，其治疗潜力在头颈部鳞状细胞癌（HNSCC）中受到了广泛关注，HNSCC是一种因发病率高、复发频繁和预后不良而臭名昭著的恶性肿瘤。本综述系统地阐述了铁死亡在HNSCC发病机制和治疗中的分子基础，重点关注四个相互关联的轴：（1）铁稳态破坏，以铁外流通道铁转运蛋白（FPN）失调为例；（2）脂质过氧化动力学，由SLC7A11等关键调节因子介导；（3）线粒体重塑，包括铁死亡执行过程中的结构和功能改变；（4）关键信号级联反应，特别是PI3K-AKT-mTOR途径，它协调细胞的生存和死亡决定。治疗探索已确定铁死亡诱导剂（如erastin）是破坏HNSCC细胞氧化还原平衡的有前景的药物，而药物抑制剂有望减轻脱靶毒性。值得注意的是，将铁死亡调节与传统疗法或其他程序性细胞死亡机制相结合的联合策略显示出协同疗效，凸显了精准肿瘤学的范式转变。本研究旨在为HNSCC中的铁死亡提供一个机制框架，将临床前见解与转化机会联系起来。通过阐明上下文依赖的调控网络并优化治疗靶点，我们提出了克服治疗耐药性的新策略，最终改善HNSCC患者的临床结局和生活质量。
