Targeting hnRNPC suppresses thyroid follicular epithelial cell apoptosis and necroptosis through m6A-modified ATF4 in autoimmune thyroid disease

• Published in: Pharmacological research Vol. 196; p. 106933
• Main Authors: Mo, Ke, Chu, Yongli, Liu, Yang, Zheng, Guibin, Song, Kaiyu, Song, Qiong, Zheng, Haitao, Tang, Yuxiao, Tian, Xinghan, Yao, Wenjie, Fang, Han, Wang, Kejian, Jiang, Yongqiang, Yang, Dengfeng, Chen, Yixuan, Huang, Chengyu, Li, Ting, Qu, Hongmei, Song, Xicheng, Zhou, Jin
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.10.2023; Elsevier
• Subjects: Apoptosis; ATF4; Autoimmune thyroid disease; HnRNPC; N6-methyladenosine; Necroptosis; Autoimmune thyroid disease; N6-methyladenosine; HnRNPC; Necroptosis; Apoptosis; ATF4
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2023.106933

Both environmental and genetic factors contribute to the etiology of autoimmune thyroid disease (AITD) including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). However, the exact pathogenesis and interactions that occur between environmental factors and genes remain unclear, and therapeutic targets require further investigation due to limited therapeutic options. To solve such problems, this study utilized single-cell transcriptome, whole transcriptome, full-length transcriptome (Oxford nanopore technology), and metabolome sequencing to examine thyroid lesion tissues from 2 HT patients and 2 GD patients as well as healthy thyroid tissue from 1 control subject. HT patients had increased ATF4-positive thyroid follicular epithelial (ThyFoEp) cells, which significantly increased endoplasmic reticulum stress. The enhanced sustained stress resulted in cell death mainly including apoptosis and necroptosis. The ATF4-based global gene regulatory network and experimental validation revealed that N6-methyladenosine (m6A) reader hnRNPC promoted the transcriptional activity, synthesis, and translation of ATF4 through mediating m6A modification of ATF4. Increased ATF4 expression initiated endoplasmic reticulum stress signaling, which when sustained, caused apoptosis and necroptosis in ThyFoEp cells, and mediated HT development. Targeting hnRNPC and ATF4 notably decreased ThyFoEp cell death, thus ameliorating disease progression. Collectively, this study reveals the mechanisms by which microenvironmental cells in HT and GD patients trigger and amplify the thyroid autoimmune cascade response. Furthermore, we identify new therapeutic targets for the treatment of autoimmune thyroid disease, hoping to provide a potential way for targeted therapy. [Display omitted] •A global single-cell atlas is established in autoimmune thyroid disease.•m6A reader hnRNPC promotes the formation of ThyFoEp_ATF4 subpopulation.•ATF4 overexpression causes apoptosis and necroptosis of ThyFoEp cells.•Endoplasmic reticulum stress is activated in the B-plasma cell lineage of HT.•Endothelial cell proliferation mediates thyroid hypervascularization in GD.