雷公藤红素经AMOTL依赖的Hippo/YAP通路改善重度激素抵抗型哮喘气道重塑
2026/07/31
摘要
背景：重度激素抵抗型哮喘（SSRA）常伴有不可逆的气道重塑，后者是导致持续气流受限和治疗反应不佳的重要原因。雷公藤红素（CEL）有抗炎及组织保护作用，但其在激素抵抗型哮喘气道重塑中的作用仍待阐明。
目的：评估雷公藤红素对SSRA的疗效，并进一步探讨依赖 AMOTL1 的 Hippo/Yes 相关蛋白（YAP）/ 含 PDZ 结合基序的转录共激活因子（TAZ）信号通路是否参与抗气道重塑作用。
方法：通过OVA/CFA/LPS致敏和激发建立SSRA小鼠模型，并分别给予雷公藤红素或地塞米松治疗。通过检测气道高反应性、肺组织病理学、炎症细胞浸润、黏液分泌、胶原沉积及肺组织蛋白质组学评估疗效。采用骨桥蛋白（OPN）刺激的人支气管平滑肌细胞构建重塑模型，进行AMOTL1过表达和敲低实验，并在SSRA小鼠中构建气道局部AMOTL1敲低模型。
结果：雷公藤红素改善了SSRA小鼠的气道高反应性，抑制气道炎症，黏液分泌及胶原沉积。蛋白质组学分析显示，AMOTL1在SSRA模型中表达下调，而经雷公藤红素治疗后表达水平恢复。在平滑肌中，雷公藤红素抑制骨桥蛋白诱导的细胞增殖、迁移及细胞外基质生成，同时重新激活Hippo信号通路并抑制YAP/TAZ活性。敲低AMOTL1会减弱雷公藤红素的抗气道重塑作用，而过表达AMOTL1可重现其保护作用。体内实验中，敲低Amotl1减弱了雷公藤红素对SSRA相关气道重塑的改善作用。
结论：雷公藤红素通过激活AMOTL1/Hippo/YAP信号通路，有效抑制激素抵抗型哮喘的气道炎症和气道重塑，为该类难治性哮喘提供了新的治疗思路。
关键词：AMOTL1；气道重塑；雷公藤红素；Hippo信号通路；重度激素抵抗型哮喘
Abstract
Background: Severe steroid-resistant asthma (SSRA) is frequently associated with irreversible airway remodeling (AR), which contributes to persistent airflow limitation and poor therapeutic responsiveness. Celastrol (CEL) exhibits anti-inflammatory and tissue-protective properties; however, its role in steroid-resistant AR remains unclear.
Purpose: This study aimed to evaluate the therapeutic effects of CEL on SSRA and to determine whether AMOTL1-dependent Hippo/Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling contributes to its anti-remodeling activity.
Methods: SSRA mice were generated via OVA/CFA/LPS sensitization and challenge and treated with CEL or dexamethasone. Airway hyperresponsiveness (AHR), lung histopathology, inflammatory cell infiltration, mucus secretion, collagen deposition, and lung proteomic profiles were evaluated. Osteopontin (OPN)-stimulated human bronchial smooth muscle cells (HBSMCs) were used to model airway smooth muscle remodeling. AMOTL1 gain- and loss-of-function studies were conducted in HBSMCs, and airway-local Amotl1 knockdown was introduced into SSRA mice.
Results: CEL improved AHR and suppressed airway inflammation, mucus production, and collagen accumulation in SSRA mice. Proteomic analysis revealed that AMOTL1 was downregulated in SSRA and restored by CEL treatment. In HBSMCs, CEL suppressed OPN-induced proliferation, migration, and extracellular matrix production, accompanied by Hippo pathway reactivation and YAP/TAZ inhibition. AMOTL1 knockdown in HBSMCs attenuated these anti-remodeling effects, whereas AMOTL1 overexpression recapitulated the protective effects of CEL. In vivo, Amotl1 knockdown blunted CEL-mediated improvement in SSRA-associated AR.
Conclusion: CEL alleviates steroid-resistant AR through AMOTL1-dependent restoration of Hippo/YAP signaling, highlighting the AMOTL1/Hippo/YAP axis as a potential therapeutic target in SSRA.
Keywords: AMOTL1; Airway remodeling; Celastrol; Hippo pathway; Severe steroid-resistant asthma
背景：重度激素抵抗型哮喘（SSRA）常伴有不可逆的气道重塑，后者是导致持续气流受限和治疗反应不佳的重要原因。雷公藤红素（CEL）有抗炎及组织保护作用，但其在激素抵抗型哮喘气道重塑中的作用仍待阐明。
目的：评估雷公藤红素对SSRA的疗效，并进一步探讨依赖 AMOTL1 的 Hippo/Yes 相关蛋白（YAP）/ 含 PDZ 结合基序的转录共激活因子（TAZ）信号通路是否参与抗气道重塑作用。
方法：通过OVA/CFA/LPS致敏和激发建立SSRA小鼠模型，并分别给予雷公藤红素或地塞米松治疗。通过检测气道高反应性、肺组织病理学、炎症细胞浸润、黏液分泌、胶原沉积及肺组织蛋白质组学评估疗效。采用骨桥蛋白（OPN）刺激的人支气管平滑肌细胞构建重塑模型，进行AMOTL1过表达和敲低实验，并在SSRA小鼠中构建气道局部AMOTL1敲低模型。
结果：雷公藤红素改善了SSRA小鼠的气道高反应性，抑制气道炎症，黏液分泌及胶原沉积。蛋白质组学分析显示，AMOTL1在SSRA模型中表达下调，而经雷公藤红素治疗后表达水平恢复。在平滑肌中，雷公藤红素抑制骨桥蛋白诱导的细胞增殖、迁移及细胞外基质生成，同时重新激活Hippo信号通路并抑制YAP/TAZ活性。敲低AMOTL1会减弱雷公藤红素的抗气道重塑作用，而过表达AMOTL1可重现其保护作用。体内实验中，敲低Amotl1减弱了雷公藤红素对SSRA相关气道重塑的改善作用。
结论：雷公藤红素通过激活AMOTL1/Hippo/YAP信号通路，有效抑制激素抵抗型哮喘的气道炎症和气道重塑，为该类难治性哮喘提供了新的治疗思路。
关键词：AMOTL1；气道重塑；雷公藤红素；Hippo信号通路；重度激素抵抗型哮喘
（南方医科大学南方医院 倪钰 凌嘉骏 赵海金）
(Jialiang Sun, Ziyu Liu et al. Celastrol alleviates airway remodeling in severe steroid-resistant asthma via AMOTL1-dependent restoration of Hippo/YAP signaling. Phytomedicine. 2026 Jun 29:159:158527. doi: 10.1016/j.phymed.2026.158527.)
Abstract
Background: Severe steroid-resistant asthma (SSRA) is frequently associated with irreversible airway remodeling (AR), which contributes to persistent airflow limitation and poor therapeutic responsiveness. Celastrol (CEL) exhibits anti-inflammatory and tissue-protective properties; however, its role in steroid-resistant AR remains unclear.
Purpose: This study aimed to evaluate the therapeutic effects of CEL on SSRA and to determine whether AMOTL1-dependent Hippo/Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling contributes to its anti-remodeling activity.
Methods: SSRA mice were generated via OVA/CFA/LPS sensitization and challenge and treated with CEL or dexamethasone. Airway hyperresponsiveness (AHR), lung histopathology, inflammatory cell infiltration, mucus secretion, collagen deposition, and lung proteomic profiles were evaluated. Osteopontin (OPN)-stimulated human bronchial smooth muscle cells (HBSMCs) were used to model airway smooth muscle remodeling. AMOTL1 gain- and loss-of-function studies were conducted in HBSMCs, and airway-local Amotl1 knockdown was introduced into SSRA mice.
Results: CEL improved AHR and suppressed airway inflammation, mucus production, and collagen accumulation in SSRA mice. Proteomic analysis revealed that AMOTL1 was downregulated in SSRA and restored by CEL treatment. In HBSMCs, CEL suppressed OPN-induced proliferation, migration, and extracellular matrix production, accompanied by Hippo pathway reactivation and YAP/TAZ inhibition. AMOTL1 knockdown in HBSMCs attenuated these anti-remodeling effects, whereas AMOTL1 overexpression recapitulated the protective effects of CEL. In vivo, Amotl1 knockdown blunted CEL-mediated improvement in SSRA-associated AR.
Conclusion: CEL alleviates steroid-resistant AR through AMOTL1-dependent restoration of Hippo/YAP signaling, highlighting the AMOTL1/Hippo/YAP axis as a potential therapeutic target in SSRA.
Keywords: AMOTL1; Airway remodeling; Celastrol; Hippo pathway; Severe steroid-resistant asthma
