编辑丨王多鱼 排版丨水成文 在生命的微观世界中，清晰"看见"驱动生命运转的分子机器——蛋白质、核酸及其他生物大分子，是理解 其功能、揭示疾病机制和开发创新药物的关键。近年来， 冷冻电子显微镜技术 （cryo-EM） 掀起了一场" 分辨率革命 "，使得科学家可以在原子尺度上捕捉生命机器的瞬时三维图像，极大程度加速了生物学各领域 的分子机理研究。然而，这一强大技术长期面临一个严重瓶颈： 数据处理流程复杂、耗时且高度依赖专家 经验。 2025 年 11 月 27 日，西湖大学 申怀宗 、 原发杰 团队合作 （ 颜阳 、 范诗奇 为论文共同第一作者 ） ，在 Nature Methods 期刊发表了题为： A comprehensive foundation model for cryo-EM image processing 的研究论文。 Cryo-IEF ： 让 AI " 理解 " 冷冻电镜图像 面对上述挑战，以往 AI 方案多聚焦于开发针对 冷冻电镜数据处理特 定步骤的 "工具"，如自动 挑选蛋白 质 颗粒或 进行图像 二维分类 筛选 ，但 完整的数据处理流程仍 需大量人工干预，未能实现 完全 自动 化。西湖大 ...

Core Viewpoint - The article discusses the molecular mechanisms of the SIFI protein in the integrated stress response (ISR), highlighting its role in managing cellular stress and preventing neurodegenerative diseases [4][5][6]. Group 1: Stress Response Mechanism - Chronic stress activation can damage cell survival and lead to severe degenerative diseases, prompting organisms to deploy factors like E3 ubiquitin ligase SIFI to terminate stress signaling and maintain cellular homeostasis [2][3]. - When cells encounter stress, such as mitochondrial damage or protein misfolding, they activate ISR to pause non-essential activities and focus resources on repair. If the stress response is not timely deactivated, it can lead to cell starvation and diseases like cerebellar ataxia and early-onset dementia [5][6]. Group 2: Role of SIFI - SIFI is an E3 ubiquitin ligase complex responsible for marking HRI and damaged proteins for degradation after stress is alleviated, thus restarting normal cellular functions [7][8]. - The research team utilized cryo-electron microscopy to capture the high-resolution structure of SIFI, revealing a giant scaffold structure composed of UBR4, KCMF1, and calmodulin, which is comparable in size to ribosomes (1.3 MDa) [9]. Group 3: SIFI's Mechanism of Action - SIFI operates through a multi-step process: 1. It performs a broad-spectrum quality check by capturing various stress-related proteins [12]. 2. KCMF1 initiates the tagging of substrates with the first ubiquitin label [13]. 3. UBR4 facilitates a chain reaction to form a degradation signal chain, essential for controlling stress signaling [14]. Group 4: Implications for Disease and Therapy - Mutations in UBR4 found in patients disrupt SIFI's function, leading to neurodegenerative conditions, but restoring SIFI function or inhibiting HRI can reverse pathological phenotypes in mouse models [15]. - The broad substrate binding capability of SIFI provides a template for designing new PROTAC molecules, potentially overcoming challenges in targeting "undruggable" proteins in cancer therapy [16].