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线粒体ABHD11的抑制驱动着固醇代谢以调节T细胞效应器功能

Benjamin J Jenkins¹, Yasmin R Jenkins¹, Fernando M Ponce-Garcia¹

¹Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, UK.

Nature communications

|November 3, 2025

概括

向含有α/β-基酶域的蛋白11 (ABHD11) 通过增加24,25-epoxycholesterol和激活肝X受体来抑制T细胞炎症. 这一临床前发现表明ABHD11是自身免疫性疾病的潜在药物标.

科学领域:

免疫学免疫学免疫学
代谢途径代谢途径
药物发现药物发现

背景情况:

含有α/β-氨酸酶域的蛋白质11 (ABHD11) 是一种线粒体氨酸酶,对α-氨酸酸脱酶 (α-KGDH) 功能至关重要.
在CD4+T细胞中的ABHD11表达与类风湿性关节炎 (RA) 缓解相关,但其在T细胞代谢和功能中的作用尚不清楚.

研究的目的:

研究ABHD11在调节T细胞代谢和功能的作用.
探索ABHD11作为T细胞介导的炎症和自身免疫疾病的潜在治疗点.

主要方法:

在人类和小鼠T细胞中抑制ABHD11的药理性抑制.
分析细胞因子的产生,24,25-环氧胆固醇 (24,25-EC) 生物合成和肝脏X受体 (LXR) 的激活.
在患有自身免疫性疾病的患者队列中评估T细胞概况.
在加速型1型糖尿病 (T1D) 的小鼠模型中评估ABHD11抑制.

主要成果:

抑制ABHD11降低了T细胞中细胞因子的产生.
由于TCA循环的妥协,抑制导致24-25-EC生物合成和LXR激活的增加.
观察到的抗炎作用在患者队列和T1D小鼠模型中一致.
向ABHD11抑制了抗原特异性T细胞细胞因子的产生,并延迟了雌性小鼠的糖尿病发病.

结论:

ABHD11在调节T细胞炎症反应方面发挥着重要作用.
抑制ABHD11为T细胞介导的炎症和T1D等自身免疫性疾病提供了有前途的治疗策略.
临床前证据支持ABHD11作为治疗自身免疫性疾病的可行药物标.

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