FABP4 as a Therapeutic Host Target Controlling SARS-CoV2 Infection

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-CoV2 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. ### Competing Interest Statement EK is co-founder, director and officer of Crescenta Biosciences and holds equity at the company. AA and FS are employees of Crescenta Biosciences. HK is co-founder, director, and consultant of Crescenta Biosciences and holds equity at the company. HK is an employee of Princeton University; All work of HK included herein was performed as a consultant for Crescenta, independent of Princeton University. HK, EK and GSH are inventors on patent application that includes CRE-14. GSH is a scientific advisor, receives compensation and holds equity at Crescenta Biosciences. Other authors declare no competing interests.