苏州大学胡丽芳小组的研究开发出了ADT-OH促进小胶质细胞的线粒体自噬并抑制细胞内mtDNA-cGAS-STING炎症级联反应。相关论文于2026年4月9日发表在《中国药理学报》杂志上。

在这项研究中，课题组研究人员报道了ADT-OH在小胶质细胞中引起有丝分裂通量。mt-Keima探针显示，线粒体标记蛋白（TOM20、COXIV和HSP60）的稳态水平降低，线粒体裂变动力学增强，线粒体易位进入溶酶体，证明了这一点。在机制上，其促进线粒体自噬的作用依赖于SQR介导的线粒体解偶联和随后的PINK1-PARKIN信号的激活。重要的是，ADT-OH消除了α-突触核蛋白预形成原纤维（α-Syn PFF）挑战的小胶质细胞中功能失调线粒体的积累和随后线粒体DNA的细胞质释放，从而减弱了cGAS-STING途径的激活和下游炎症介质的产生。

此外，全身给药ADT-OH可抑制α-Syn过表达PD小鼠的小胶质细胞活化和cGAS表达，从而减轻中脑多巴胺能神经元的损失，改善运动协调缺陷。总之，他们的研究结果表明，ADT-OH通过增强线粒体自噬和抑制小胶质细胞介导的神经炎症，在PD模型中发挥了强大的神经保护作用，无论是在体外还是体内。

据悉，由遗传易感性或环境损害驱动的线粒体功能障碍有助于神经退行性疾病的发病机制，包括帕金森病（PD）。线粒体自噬是一种选择性途径，消除功能失调的线粒体，线粒体自噬诱导剂具有治疗神经变性的希望。然而，特异性的、临床可行的诱导剂仍然有限。ADT-OH是一种缓释H₂S化合物，最近被报道通过硫化物-醌氧化还原酶（SQR）介导的H₂S氧化诱导线粒体解偶联。

附：英文原文

Title: ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia

Author: Hou, Xiao-ou, Wang, Miao, Deng, Rong, Lu, Yi-fan, Zhang, Jin-ru, Ren, Li, Chen, Jing, Liu, Chun-feng, Yang, Ya-ping, Hu, Li-fang

Issue&Volume: 2026-04-09

Abstract: Mitochondrial dysfunction, driven by genetic susceptibility or environmental insults, contributes to the pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Mitophagy is a selective pathway that eliminates dysfunctional mitochondria, and mitophagy inducers hold therapeutic promise for neurodegeneration. However, the arsenal of specific, clinically viable inducers remains limited. ADT-OH, a slow-release H2S compound, was recently reported to induce mitochondrial uncoupling through sulfide-quinone oxidoreductase (SQR)-mediated oxidation of H2S. In this study, we report that ADT-OH elicits mitophagic flux in microglia. This is evidenced by the reduced steady-state levels of mitochondrial marker proteins (TOM20, COXIV, and HSP60), enhanced mitochondrial fission dynamics, and mitochondrial translocation into lysosomes, as visualized by the mt-Keima probe. Mechanistically, its mitophagy-promoting effect is dependent on SQR-mediated mitochondrial uncoupling and subsequent activation of PINK1-PARKIN signaling. Importantly, ADT-OH abrogates the accumulation of dysfunctional mitochondria and the subsequent cytosolic release of mitochondrial DNA in α-synuclein preformed fibrils (α-Syn PFF)-challenged microglia, thereby blunting the activation of the cGAS-STING pathway and the downstream production of inflammatory mediators. Furthermore, systemic administration of ADT-OH dampened microglial activation and cGAS expression in α-Syn-overexpressing PD mice, thereby mitigating the loss of midbrain dopaminergic neurons and ameliorating motor coordination deficits. Collectively, our findings demonstrate that ADT-OH exerts robust neuroprotective effects in PD models, both in vitro and in vivo, by enhancing mitophagy and inhibiting microglia-mediated neuroinflammation.

DOI: 10.1038/s41401-026-01789-7

Source: https://www.nature.com/articles/s41401-026-01789-7