中山大学梁晓雨课题组的最新研究提出了TOLLIP靶向携带GSDME-NT的内吞囊泡自噬，调节焦亡和化疗效果。2026年3月9日，国际知名学术期刊《自然—细胞生物学》发表了这一成果。

本研究发现，自噬可以消除位于细胞膜不同位置的GSDME （GSDME-NT）孔形成的N端，抑制焦亡。至关重要的是，质膜上的GSDME-NT通过内吞内化被消除，其中GSDME-NT装载的囊泡被靶向并作为完整的单位降解。具体来说，质膜上的GSDME-NT孔诱导胞吞作用，产生携带GSDME-NT的内吞但有渗漏的囊泡。泄漏阻止了酸化，需要通过自噬进一步降解。胞吞后，囊泡膜上的GSDME-NT被钙激活的E3连接酶NEDD4L标记为泛素。这些标记的囊泡被TOLLIP识别，引导随后的自噬体形成，并使其进一步酸化，与溶酶体结合，最终降解GSDME-NT。

此外，在几种肿瘤模型中，通过靶向TOLLIP干扰自噬或干扰GSDME-NT囊泡的识别可增加肿瘤细胞焦亡，激活抗肿瘤免疫并促进化疗疗效。

据介绍，焦亡是否可控和可逆仍然是一个谜。

附：英文原文

Title: TOLLIP targets GSDME-NT-carrying endocytic vesicles for autophagy to regulate pyroptosis and chemotherapy efficacy

Author: Xu, Zhimin, Li, Zhe, Deng, Zhenji, Ding, Cong, Wu, Jiawei, Zhang, Chuqing, Wei, Hanmiao, He, Tingxiang, Long, Liufen, Tang, Linglong, Ma, Jun, Liang, Xiaoyu

Issue&Volume: 2026-03-09

Abstract: Whether pyroptosis is controllable and reversible remains an enigma. Here we revealed that autophagy could eliminate the pore-formed N terminus of GSDME (GSDME-NT) located on membranes at different locations, suppressing pyroptosis. Crucially, GSDME-NT on the plasma membrane was eliminated through endocytic internalization, where GSDME-NT-laden vesicles were targeted and degraded as intact units. Specifically, GSDME-NT pores on the plasma membrane induced endocytosis, generating endocytosed but leaky vesicles carrying GSDME-NT. Leakage prevented acidification, necessitating further degradation through autophagy. Upon endocytosis, GSDME-NT on the vesicle membrane was labelled with ubiquitin by calcium-activated E3 ligase NEDD4L. These labelled vesicles were recognized by TOLLIP, guiding subsequent autophagosome formation, and enabling further acidification, fusion with lysosomes and eventual GSDME-NT degradation. Furthermore, in several tumour models, either disturbing autophagy or interfering with the recognition of GSDME-NT vesicles by targeting TOLLIP increased tumour cell pyroptosis, activating antitumour immunity and promoting chemotherapeutic efficacy.

DOI: 10.1038/s41556-026-01902-2

Source: https://www.nature.com/articles/s41556-026-01902-2