Mechanosensation promotes broad-spectrum antiviral defense through membrane remodeling

The capacity to sense mechanical stimuli represents one of the most fundamental characteristics of life, enabling organisms to navigate their environment. Here, we identify the mechano-antiviral response system (MARS), a Piezo1-mediated pathway that confers broad-spectrum antiviral immunity distinct from known innate immune systems. Using enterovirus D68 (EV-D68) as a model, we demonstrate that cellular compression or fluid pressure activates Piezo1-dependent antiviral resistance in non-immune cells. Piezo1 functions as a natural antiviral factor, and its pharmacological activation protects against multiple clinical isolates of EV-D68. Mechanistically, the activation of the biomechanical-Piezo1 axis results in a marked reduction in host cell membrane fluidity, a critical determinant for viral entry. Consequently, MARS restricts the replication of diverse viruses, including rhinovirus and influenza. In vivo studies reveal that Piezo1 agonists or mechanical stimuli alleviate EV-D68-induced neurological damage and lethality. Our findings underscore MARS-mediated membrane remodeling as a non-canonical antiviral strategy, expanding the paradigms of immune stimulation.