Lung epithelial endothelin-1 drives iron dysregulation and skeletal injury after SARS-CoV-2 infection

Post-COVID musculoskeletal disorders are not uncommon; yet the mechanisms linking SARS-CoV-2 respiratory infection to skeletal injury remain unclear. Here, we identify a lung-joint axis in which elevated endothelin-1 (ET-1) in alveolar type Ⅱ cells (AT2) disrupts iron homeostasis and contributes to cartilage and growth plate injury after SARS-CoV-2 infection. Through scRNA sequencing and histopathological analysis of COVID-19 patients' and infected hamsters' lung and joint tissues, elevated ET-1 is linked to dysregulated iron homeostasis and iron accumulation. Mechanistically, genetically silencing ET-1 in lung epithelial cells attenuated viral spike-induced iron overload, while iron chelation improved the viability of chondrocytes in vitro. Therapeutically, the FDA-approved endothelin receptor antagonist, macitentan, protected infected hamsters from joint damage by reducing iron overload-associated chondrocyte dropout in both acute and subacute phase of infection in vivo. Our findings reveal the pathological ET-1 in lung-joint axis and highlight its receptors as therapeutic target for post-COVID skeletal sequelae.