Liu Bingxin, Tian Xiaoyan, Li Linrun, Jiang Na, Cheng Min, Zhu Jin, Wu Zhiwei
Center for Public Health Research, Medical School of Nanjing University, Nanjing, China.
The Department of Immunology, Huadong Medical Institute of Biotechnique, Nanjing, China.
Autophagy. 2025 May 14:1-14. doi: 10.1080/15548627.2025.2503564.
Severe fever with thrombocytopenia syndrome (SFTS) is a widely prevalent infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV). SFTSV infection carries a high mortality rate and has emerged to be a public health concern. SFTSV infection could induce many classical cell death pathways. Ferroptosis, a novel iron-dependent form of regulated cell death, is shown to participate in various biological processes and is considered as a new therapeutic target. In the current study, we reported that SFTSV infection perturbed the classical redox cycle by downregulating the expression of GPX4, SLC7A11 and GSH, and increasing the level of reactive oxygen species (ROS) and malondialdehyde (MDA). Interestingly, we observed that the elevation of mRNA m6A modification after SFTSV infection and mutation of the m6A-sites significantly rescued SFTSV infection-induced ferritinophagy. We further found that the NSs protein of SFTSV played a major role in driving the ferritinophagy. Finally, we found that ferroptosis inhibitor ferrostatin-1 prevented ferroptosis and suppressed SFTSV infection both and models. In summary, our study demonstrated that SFTSV infection could induce ferroptosis in liver, and m6A modified AT5 mediated ferritinophagy to facilitate this process. Targeting ferroptosis may serve as a potential therapy for the treatment of SFTS. ATG5: autophagy related 5; Baf-A1: bafilomycin A; Fer-1: ferrostatin-1; Fe: ferrous iron; FTH1: ferritin heavy chain 1; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic - pyruvic transaminase; GSH: glutathione; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; ROS: reactive oxygen species; SFTSV: severe fever with thrombocytopenia virus; SQSTM1/p62: sequestosome 1.
严重发热伴血小板减少综合征（SFTS）是由严重发热伴血小板减少综合征病毒（SFTSV）引起的一种广泛流行的传染病。SFTSV感染死亡率高，已成为一个公共卫生问题。SFTSV感染可诱导多种经典的细胞死亡途径。铁死亡是一种新的铁依赖性调节性细胞死亡形式，已被证明参与各种生物学过程，并被视为一个新的治疗靶点。在本研究中，我们报道SFTSV感染通过下调GPX4、SLC7A11和GSH的表达，增加活性氧（ROS）和丙二醛（MDA）水平，扰乱经典的氧化还原循环。有趣的是，我们观察到SFTSV感染后mRNA m6A修饰升高，m6A位点突变显著挽救了SFTSV感染诱导的铁自噬。我们进一步发现，SFTSV的NSs蛋白在驱动铁自噬中起主要作用。最后，我们发现铁死亡抑制剂铁抑素-1在细胞和动物模型中均能预防铁死亡并抑制SFTSV感染。总之，我们的研究表明，SFTSV感染可诱导肝脏铁死亡，m6A修饰的ATG5介导铁自噬以促进这一过程。靶向铁死亡可能是治疗SFTS的一种潜在疗法。ATG5：自噬相关5；Baf-A1：巴弗洛霉素A；Fer-1：铁抑素-1；Fe：亚铁；FTH1：铁蛋白重链1；GOT1/AST：谷草转氨酶1；GPT/ALT：谷丙转氨酶；GSH：谷胱甘肽；MAP1LC3/LC3：微管相关蛋白1轻链3；MDA：丙二醛；NCOA4：核受体辅激活因子4；ROS：活性氧；SFTSV：严重发热伴血小板减少病毒；SQSTM1/p62：聚集体蛋白1
