具体而言，细胞在营养匮乏时，名为"乙酰辅酶A"的"神秘信使"出动，它会绕过科学家们熟知的AMPK 和mTOR这两条营养感知的"经典主干道"，独辟蹊径地将"饥饿"信号直抵细胞能量工厂——线粒体，指 挥"哨兵"NLRX1作出响应。这项发现不仅解释了适度饥饿如何触发身体的积极反应，还将为未来对抗 代谢性疾病、癌症乃至延缓衰老开辟了一条充满想象的全新研究道路。 近年来，"轻断食"之风流行，人们通过控制进食时间让身体保持适度饥饿，以此调动脂肪、稳定血糖， 清除体内的老废代谢物。这背后的原因是什么？11月13日，复旦大学雷群英团队在国际学术期刊《自 然》(Nature)在线发表研究论文，提供了解释。 这项历经近10年探索的研究，首次揭示了乙酰辅酶A作为"代谢信使"的非经典功能，突破传统认知，发 现其可直接调控线粒体自噬，为克服胰腺癌KRAS抑制剂耐药提供了全新治疗靶点，在代谢生物学与肿 瘤学交叉领域取得突破性进展。 复旦大学基础医学院/肿瘤研究所教授雷群英回忆，2016年年底她就与团队成员立下"flag"：要做不依赖 经典代谢感知通路的创新研究。团队模拟人体"温和饥饿"环境，用接近人体过夜饥饿的营养成分配制培 养基。实验 ...

Core Insights - The research published by Fudan University reveals a novel signaling function of Acetyl-Coenzyme A (AcCoA) in regulating mitophagy through the receptor NLRX1, independent of classical pathways like AMPK and mTOR [3][14][16] - This discovery provides new potential targets and strategies for overcoming resistance to KRAS inhibitors in cancer treatment [3][14][16] Group 1: Mechanism of AcCoA in Mitophagy - AcCoA levels decrease during nutrient deprivation, such as short-term fasting, leading to the activation of mitophagy [5][6] - NLRX1 is identified as a key mediator that directly binds to AcCoA, regulating its signaling role in mitophagy [8][11] Group 2: Experimental Validation - In animal models, fasting resulted in a significant decrease in AcCoA levels in tissues, correlating with increased mitophagy [11] - Supplementing with acetate or knocking out NLRX1 gene can block the fasting-induced mitophagy, indicating the critical role of AcCoA and NLRX1 in this process [11][12] Group 3: Implications for Cancer Treatment - The study indicates that KRAS inhibitors downregulate ACLY expression, reducing AcCoA levels and triggering NLRX1-dependent mitophagy, which may contribute to cancer cell resistance [14] - Short-term fasting may have dual effects in cancer treatment, potentially enhancing immune response while also promoting resistance through mitophagy [14][16] Group 4: Future Directions - Targeting the AcCoA-NLRX1 signaling axis may enhance cancer treatment efficacy and could have implications in various metabolic and neurodegenerative diseases [16]

撰文丨王聪 编辑丨王多鱼 排版丨水成文 尿石素 A （Urolithin A，UA） 是由富含 鞣花单宁 （例如 石榴 、树莓等） 的食物在肠道菌群中代谢产生 的化合物，可以激活线粒体自噬，改善线粒体健康。 2022 年 10 月，德国法兰克福大学医院 Florian Greten 团队 在 Immunity 期刊发表论文 【1】 。该研究显 示， 尿石素 A （UA） 能够通过 激活线粒体自噬 ，促进 T 记忆干细胞 （T scm ） 扩增，为免疫系统提供 恢复活力、不耗竭的 T 细胞， 从而通过直接调控免疫系统来抑制癌症生长。 2025 年 10 月 31 日， Florian Greten 团队在 Nature Aging 期刊发表了题为： Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial 的研究论 文。 这项 随机、双盲、安慰剂对照的临床试验表明，短期 （4 周） 口服 尿石素 A （每天 1000 毫克） ， 可 调控人体免 ...

Core Viewpoint - The research highlights the role of dietary flavonoid quercetin and its microbial metabolite DOPAC in enhancing CD8⁺ T cell anti-tumor immunity, suggesting DOPAC as a potential candidate for cancer immunotherapy [2][8]. Group 1: Mechanism of Action - Quercetin, when metabolized by gut microbiota, produces DOPAC, which enhances CD8⁺ T cell anti-tumor immunity through NRF2-mediated mitophagy [3][4]. - DOPAC binds directly to KEAP1 protein, disrupting its interaction with NRF2, thereby preventing KEAP1-mediated NRF2 degradation [4]. - Increased NRF2 activity leads to enhanced transcription of BNIP3, promoting mitophagy and improving the adaptability of CD8⁺ T cells in the tumor microenvironment [4][6]. Group 2: Synergistic Effects - DOPAC exhibits a synergistic effect with immune checkpoint blockade (ICB) therapy, further inhibiting tumor growth [5][6]. Group 3: Implications for Cancer Treatment - The findings underscore the importance of dietary nutrients and their microbial metabolites in regulating anti-tumor immune responses, positioning DOPAC as a promising candidate for cancer immunotherapy [8].

Core Insights - The article discusses the significant role of mitochondria in mammalian development and introduces a new method for enforced mitophagy that allows for the reduction or complete removal of mitochondria, revealing their influence on pluripotency and embryonic development [3][15]. Group 1: Research Findings - The study published by Professor Wu Jun's team at the University of Texas Southwestern Medical Center demonstrates that enforced mitophagy can lead to a reduction in mitochondrial quantity, which subsequently delays pre-implantation embryonic development in mice [3][11]. - The research indicates that pluripotent stem cells (PSCs) lacking mitochondria can survive for 3-5 days in vitro but cease to divide, suggesting that these cells can compensate for the absence of mitochondria by taking over energy production and other functions typically performed by mitochondria [8][13]. - The study also reveals that the enforced mitophagy method can be applied across different species and cell types, potentially opening new avenues for research and treatment of mitochondrial diseases [8][15]. Group 2: Methodology - The enforced mitophagy technique involves expressing the PRKN protein in cells, which promotes the degradation of dysfunctional mitochondria, followed by treatment with mitochondrial uncouplers to stimulate extensive mitophagy [6][8]. - The research team successfully generated PSCs devoid of mitochondria and assessed the gene expression changes, finding that 788 genes became less active while 1696 genes became more active, indicating a shift in cellular function [8][13]. - The study further explores the fusion of human PSCs with those from non-human primates, revealing that these hybrid cells selectively retain human mitochondrial DNA, demonstrating the interchangeability of mitochondrial support for pluripotency across species [9][13]. Group 3: Implications - The findings suggest that a significant reduction in mitochondrial content can hinder embryonic development, with a 65% loss leading to implantation failure and a 33% loss resulting in developmental delays [11][13]. - The research provides a powerful tool for investigating the roles of mitochondria in cellular functions, organ development, aging, and evolutionary biology, potentially impacting future therapeutic strategies for mitochondrial diseases [15].