AUTHOR=Xiao Yuzhou , Liu Chunqi , Wang Xiaojie , Li Hongchun , Wang Liang , Gou Kun , Liu Xingchen , Guan Xinqi , Zhou Xia , He Xiumei , Zhao Yue , Tao Lei , Pan Xiaodan , Jiang Linhong , Chen Yaxing , Liu Huan , Dai Yanping , Bu Qian , Qin Meng , Zhu Ruiming , Chen Bo , Flores Angelo D. , Zhao Yinglan , Cen Xiaobo 

TITLE=Dysregulated glycerophospholipid metabolism in amygdala may mediate favipiravir-induced anxiety-like behaviors in mice

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1491150

DOI=10.3389/fphar.2025.1491150

ISSN=1663-9812

ABSTRACT=Favipiravir, the first RNA polymerase inhibitor approved to treat resistant influenza, has been reported to be associated with central nervous system (CNS) side effects, particularly anxiety-like behavior; nevertheless, the underlying mechanism remains largely unknown. In this study, we investigated the effect of favipiravir on the neurobehavior of mice, and combined lipidomics and transcriptomics analysis to explore the mechanism underlying this effect. In behavioral tests, the mice displayed anxiety-like behaviors after oral favipiravir administration (200 mg/kg) for 7 days continuously. By lipidomics analysis, we observed that favipiravir induced a dysregulation of glycerophospholipid metabolism in the amygdala. Moreover, favipiravir significantly reduced the mRNA level of glycerol-3-phosphate acyltransferase 2 (Gpat2), the rate-limiting enzyme of glycerophospholipid synthesis. Notably, favipiravir markedly reduced the levels of docosahexaenoic acid-enriched phosphatidylethanolamine or phosphatidylcholine (DHA-PE/PC) and arachidonic acid-enriched phosphatidylethanolamine or phosphatidylcholine (AA-PE/PC), two components of glycerophospholipids, in the amygdala. The increased expression of phospholipase A2 (Pla2) may attribute to the enhanced release of arachidonic acid (AA) from AA-PE/PC. Furthermore, favipiravir altered neurite morphology and reduced neurophysiological activity in amygdala neurons in vitro. Collectively, dysregulated glycerophospholipid metabolism in the amygdala may contribute to the adverse effect of favipiravir.