撰文丨王聪 编辑丨王多鱼 排版丨水成文 整合应激反应 （ Integrated Stress Response， ISR） 是一种保守的应激反应，可维持真核细胞的内环境稳定。调节整合刺激反应 （ISR） 对包括病毒感染、癌 症和神经退行性疾病在内的多种疾病具有治疗潜力，但目前鲜有已知化合物能够在无毒副作用的情况下实现这一调节。 2025 年 7 月 11 日，Broad 研究所 James Collins 教授 、 Integrated Biosciences 公司 的 Felix Wong 、 Maxwell Wilson 等人在国际顶尖学术期刊 Cell 上 发表了题为： Optogenetics-enabled discovery of integrated stress response modulators 的研究论文 【1】 。 该研究将 光遗传学 技术用于 药物发现 ，开发了一个用于发现能够选择性调节 整合刺激反应 （ISR） 的化合物的光遗传学平台，筛选出了能够选择性消除在各种 应激压力条件下具有高 ISR 的细胞的化合物，这些化合物在体外和小鼠体内均表现出 广谱抗病毒活性 。 Felix W ...

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].