实体肿瘤已经发展出强大的铁死亡抵抗能力。然而，实体肿瘤中调控铁死亡抵抗的机制仍然不明确。在这里，我们报告了缺氧的肿瘤微环境以一种缺氧诱导因子1α (HIF-1α) 依赖的方式强烈促进实体肿瘤中的铁死亡抵抗。在缺氧下，HIF-2α与HIF-1α共同促进肿瘤铁死亡，而HIF-1α则是缺氧诱导的铁死亡抵抗的主要推动因子。机械上，HIF-1α诱导的乳酸以一种依赖于pH的方式促进铁死亡抵抗，与经典的SLC7A11和FSP1系统平行。此外，HIF-1α还增强了重要的谷氨酸转运体SLC1A1的转录，并促进半胱氨酸的摄取促进铁死亡抵抗。支持缺氧在铁死亡抵抗中的作用，沉默HIF-1α使小鼠实体肿瘤对铁死亡诱导剂产生敏感。总之，我们的研究结果揭示了缺氧促进铁死亡抵抗的机制，并确定了缓解缺氧与诱导铁死亡的组合作为实体肿瘤治疗策略的一个有希望的方法。版权所有2023 The Author(s). Elsevier Inc.发表并保留所有权利。

Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.