泛素蛋白酶体系统功能障碍会导致持续的内质网应激（ERS）和随后的细胞死亡。然而，恶性肿瘤细胞已经进化出多种机制来逃避持续的ERS。因此，鉴定肿瘤细胞如何发展对ERS的耐药机制对药物耐药性肿瘤的治疗利用非常重要。在这里，我们发现蛋白酶体抑制剂能够诱导ERS，激活铁死亡信号通路，从而诱导肿瘤细胞对ERS的适应耐受性。在机制上，发现铁死亡信号通路的激活促进了包含错折和未折叠蛋白质的外泌体的形成和分泌，这导致拯救ERS并促进肿瘤细胞的生存。铁死亡信号通路的抑制与临床使用的蛋白酶体抑制剂博瑞昔布具有协同作用，可以抑制肝细胞癌细胞在体外和体内的细胞存活率。本研究发现，ERS耐受性可以通过ERS-铁死亡信号通路-外泌体途径推动，并且对于细胞内信号传导、内质网稳态和耐药性癌症治疗具有重要的临床意义。版权所有©2023 Elsevier Inc.发表。

Dysfunction of the ubiquitin‒proteasome system can induce sustained endoplasmic reticulum stress (ERS) and subsequent cell death. However, malignant cells have evolved multiple mechanisms to evade sustained ERS. Therefore, identification of the mechanisms through which tumor cells develop resistance to ERS is important for the therapeutic exploitation of these cells for drug-resistant tumors. Herein, we found that proteasome inhibitors could induce ERS, activate ferroptosis signaling, and thereby induce the adaptive tolerance of tumor cells to ERS. Mechanistically, the activation of ferroptosis signaling was found to promote the formation and secretion of exosomes containing misfolded and unfolded proteins, which resulted in rescuing ERS and promoting tumor cell survival. The inhibition of ferroptosis signaling synergized with bortezomib, a clinically used proteasome inhibitor, to suppress the viability of hepatocellular carcinoma cells in vitro and in vivo. The present findings reveal that ERS resistance can be driven by an ERS-ferroptosis signaling-exosome pathway and have important clinical implications for intracellular signaling, ER homeostasis and drug-resistant cancer therapy.Copyright © 2023. Published by Elsevier Inc.