Influenza virus infection begins with the attachment of the viral hemagglutinin (HA) protein to sialic acid receptors on host cells, followed by entry into cells via clathrin-mediated endocytosis (CME). The study identified two membrane proteins, potassium calcium-activated channel subfamily M alpha 1 (KCα1.1) and metabotropic glutamate receptor subtype 2 (mGluR2), which are crucial for initiating and completing CME of influenza virus. Influenza virus HA directly interacts with mGluR2, using it as an endocytic receptor to initiate CME. mGluR2 interacts and activates KCα1.1, leading to F-actin polymerization, maturation of clathrin-coated pits, and completion of CME. mGluR2-knockout mice were more resistant to different influenza subtypes than wild-type mice. Blocking the interaction between HA and mGluR2 could be a promising host-directed antiviral strategy. The study also found that mGluR2 interacts with the HA genes of H5 and H7 viruses, and that mGluR2-mediated CME is a common mechanism for influenza virus internalization.Influenza virus infection begins with the attachment of the viral hemagglutinin (HA) protein to sialic acid receptors on host cells, followed by entry into cells via clathrin-mediated endocytosis (CME). The study identified two membrane proteins, potassium calcium-activated channel subfamily M alpha 1 (KCα1.1) and metabotropic glutamate receptor subtype 2 (mGluR2), which are crucial for initiating and completing CME of influenza virus. Influenza virus HA directly interacts with mGluR2, using it as an endocytic receptor to initiate CME. mGluR2 interacts and activates KCα1.1, leading to F-actin polymerization, maturation of clathrin-coated pits, and completion of CME. mGluR2-knockout mice were more resistant to different influenza subtypes than wild-type mice. Blocking the interaction between HA and mGluR2 could be a promising host-directed antiviral strategy. The study also found that mGluR2 interacts with the HA genes of H5 and H7 viruses, and that mGluR2-mediated CME is a common mechanism for influenza virus internalization.