顺铂（CDDP）广泛应用于多种癌症的治疗，但其耳毒性不容忽视，临床干预效果并不理想。组氨酸脱羧酶（HDC）是组胺合成的唯一酶。抗组胺受体药物广泛用于治疗过敏和胃肠道疾病。然而，组胺及其在内耳信号传导的具体作用尚不完全清楚。本研究利用顺铂治疗的小鼠和 HEI-OC1 听觉毛细胞系建立顺铂诱导的耳毒性 (CIO) 模型。利用组氨酸脱羧酶敲除 (HDC-/-) 小鼠和组胺受体 1 (H1R) 拮抗剂来研究 HDC/组胺/H1R 信号传导对耳毒性的影响。结果确定了小鼠毛细胞中 HDC 和 H1R 的表达。转录组学表明HDC-/-小鼠耳蜗中氧化应激相关基因的表达水平增加。此外，组胺缺乏或H1R信号传导抑制会加速HC铁死亡，这是体内和体外CIO恶化的关键因素，相反，补充外源性组胺可以逆转这些有害影响。从机制上讲，本研究揭示HDC/组胺/H1R信号传导的故障诱导NRF2表达上调，同时伴随ACSL4上调和GPX4表达下调，这是铁死亡的主要调节因素。综上所述，组胺缺乏可能通过调节 H1R 通路诱导毛细胞死亡，加剧 CIO。我们的研究结果表明了 CIO 的潜在治疗靶点。版权所有 © 2024。由 Elsevier B.V. 出版。

Cisplatin (CDDP) is extensively utilized in the management of diverse types of cancers, but its ototoxicity cannot be ignored, and clinical interventions are not ideal. Histidine decarboxylase (HDC) is the exclusive enzyme for histamine synthesis. Anti-histamine receptor drugs are ubiquitously employed in the therapeutics of allergies and gastrointestinal diseases. Yet, the specific role of histamine and its signaling in the inner ear is not fully understood. This study utilized cisplatin treated mice and HEI-OC1 auditory hair cell line to establish a cisplatin-induced ototoxicity (CIO) model. Histidine decarboxylase knockout (HDC-/-) mice and histamine receptor 1 (H1R) antagonist were utilized to investigate the influence of HDC/histamine/H1R signaling on ototoxicity. The results identified HDC and H1R expression in mouse hair cells. Transcriptomics indicated that the expression levels of oxidative stress-related genes in the cochlea of HDC-/- mice increased. Furthermore, histamine deficiency or suppression of H1R signaling accelerated HC ferroptosis, a pivotal factor underlying the aggravation of CIO in vivo and in vitro, conversely, the supplementation of exogenous histamine reversed these deleterious effects. Mechanistically, this study revealed that the malfunction of HDC/histamine/H1R signaling induced upregulation of NRF2 expression, accompanied by the upregulation of ACSL4 and downregulation of GPX4 expression, which are major regulatory factors of ferroptosis. In summary, histamine deficiency may induce hair cell death by regulating the H1R pathway and exacerbate CIO. Our findings have indicated a potential therapeutic target for CIO.Copyright © 2024. Published by Elsevier B.V.