比利时根特大学Mathieu J.M. Bertrand小组的一项最新研究提出了ATG9A介导的自噬通过限制TNFR1驱动的STING激活和ZBP1依赖的细胞死亡来预防炎症性皮肤病。这一研究成果发表在2025年10月20日出版的国际学术期刊《免疫学》上。

该课题组研究人员之前的研究表明，单核角化细胞中缺乏自噬脂质合成酶ATG9A会导致严重的皮炎和全身性炎症，其特征与人类皮肤疾病相似。课题组人员现在证明，这种疾病是由TNF引发的，但由cGAS/ STING依赖的I型干扰素（IFN）产生和随后的ZBP1依赖的细胞凋亡和坏死坏死主导。ATG9A通过参与轻链3 （LC3）依赖性和非依赖性自噬来阻止疾病的发病机制。这些结果揭示了TNF信号的另一个病理分支，为TNF驱动疾病的替代治疗干预开辟了途径。

此外，本研究揭示了LC3非依赖性自噬在抑制I型IFN产生方面的另一种病理生理功能，这种功能可触发小鼠和人类干扰素病的发展或恶化。

据介绍，肿瘤坏死因子（TNF）是一种中枢促炎细胞因子，在慢性炎症和自身免疫性疾病中具有病理作用。TNF感知驱动这些疾病发病机制的机制尚不完全清楚。

附：英文原文

Title: ATG9A-mediated autophagy prevents inflammatory skin disease by limiting TNFR1-driven STING activation and ZBP1-dependent cell death

Author: Dario Priem, Jon Huyghe, Barbara Gilbert, Simon Verdonck, Tom Delanghe, Bruno Verstraeten, Esther Hoste, Peter Vandenabeele, Jonathan Maelfait, Geert van Loo, Mathieu J.M. Bertrand

Issue&Volume: 2025-10-20

Abstract: Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine with pathologic roles in chronic inflammatory and autoimmune disorders. The mechanisms by which TNF sensing drives the pathogenesis of these diseases are not fully understood. We previously showed that the lack of the autophagic lipid scramblase ATG9A in mouse keratinocytes leads to severe dermatitis and systemic inflammation, with features resembling human skin disorders. We now demonstrate that the disease is initiated by TNF but caused by cGAS/STING-dependent type I interferon (IFN) production and subsequent ZBP1-dependent apoptosis and necroptosis. ATG9A prevented the pathogenesis of the disease by engaging both light-chain 3 (LC3)-dependent and -independent autophagy. These results uncover an additional pathological arm of TNF signaling, opening avenues for alternative therapeutic interventions for TNF-driven diseases. Moreover, this study reveals another pathophysiological function of LC3-independent autophagy in restraining type I IFN production, which triggers the development or exacerbation of an interferonopathy in mice and humans.

DOI: 10.1016/j.immuni.2025.09.019

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00430-3