Baazim Hatoon, Koyuncu Emre, Tuncman Gürol, Burak M Furkan, Merkel Lea, Bahour Nadine, Karabulut Ezgi Simay, Lee Grace Yankun, Hanifehnezhad Alireza, Karagoz Zehra Firat, Földes Katalin, Engin Ilayda, Erman Ayse Gokce, Oztop Sidika, Filazi Nazlican, Gul Buket, Ceylan Ahmet, Cinar Ozge Ozgenc, Can Fusun, Kim Hahn, Al-Hakeem Ali, Li Hui, Semerci Fatih, Lin Xihong, Yilmaz Erkan, Ergonul Onder, Ozkul Aykut, Hotamisligil Gökhan S
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Crescenta Biosciences Inc, Irvine, CA, USA.
EMBO Mol Med. 2025 Mar;17(3):414-440. doi: 10.1038/s44321-024-00188-x. Epub 2025 Jan 22.
Host metabolic fitness is a critical determinant of infectious disease outcomes. Obesity, aging, and other related metabolic disorders are recognized as high-risk disease modifiers for respiratory infections, including coronavirus infections, though the underlying mechanisms remain unknown. Our study highlights fatty acid-binding protein 4 (FABP4), a key regulator of metabolic dysfunction and inflammation, as a modulator of SARS-CoV-2 pathogenesis, correlating strongly with disease severity in COVID-19 patients. We demonstrate that loss of FABP4 function, by genetic or pharmacological means, reduces SARS-CoV-2 replication and disrupts the formation of viral replication organelles in adipocytes and airway epithelial cells. Importantly, FABP4 inhibitor treatment of infected hamsters diminished lung viral titers, alleviated lung damage and reduced collagen deposition. These findings highlight the therapeutic potential of targeting host metabolism in limiting coronavirus replication and mitigating the pathogenesis of infection.
宿主代谢健康是传染病结局的关键决定因素。肥胖、衰老和其他相关代谢紊乱被认为是包括冠状病毒感染在内的呼吸道感染的高风险疾病修饰因素，但其潜在机制仍不清楚。我们的研究强调了脂肪酸结合蛋白4（FABP4），一种代谢功能障碍和炎症的关键调节因子，作为严重急性呼吸综合征冠状病毒2（SARS-CoV-2）发病机制的调节因子，与2019冠状病毒病（COVID-19）患者的疾病严重程度密切相关。我们证明，通过基因或药理学手段丧失FABP4功能，可减少SARS-CoV-2复制，并破坏脂肪细胞和气道上皮细胞中病毒复制细胞器的形成。重要的是，用FABP4抑制剂治疗受感染的仓鼠可降低肺病毒滴度，减轻肺损伤并减少胶原蛋白沉积。这些发现突出了针对宿主代谢在限制冠状病毒复制和减轻感染发病机制方面的治疗潜力。
