AXL mediates influenza A virus entry and drives virus-induced inflammation.

Influenza A virus (IAV) infection remains a persistent global health challenge with limited antiviral drugs. Viral entry represents a potential multifaceted target for antiviral intervention; however, there is a limited number of approved inhibitors that effectively prevent IAV entry. Here, we identify the receptor tyrosine kinase AXL as an IAV functional entry factor with dual roles in viral invasion and host immune modulation. Although AXL has been previously reported as a negative regulator of inflammation, we reveal that its inhibition simultaneously reduces viral entry and virus-induced inflammatory responses. Mechanistically, AXL mediates IAV invasion via the GAS6-AXL-AKT/ERK signalling axis and distinct endocytic pathways: clathrin-mediated endocytosis in epithelial cells and macropinocytosis-dominated endocytosis in alveolar macrophages. Consistently, AXL knockout mice or early administration of an AXL inhibitor during infection markedly reduced pulmonary viral loads, attenuated virus-induced cytokine production and lung pathology, and improved survival. Beyond IAV, AXL also contributes to the entry of SARS-CoV-2, MERS-CoV, and human metapneumovirus (hMPV), suggesting its potential as a broad-spectrum host-directed antiviral target. Collectively, our findings provide the first in vivo and in vitro evidence that AXL functions dually as a viral entry factor and immune modulator, highlighting its promise as a therapeutic target to block infection and control virus-induced inflammation.