Abstract

Summary 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.