Targeting ACE2 with luteolin improves imbalance of lung epithelial sodium transport under Omicron infection.

BACKGROUND: As a progressive pathological process, pulmonary edema driven by Omicron infection is closely related to the imbalance of epithelial sodium channel (ENaC)-regulated sodium transport. Luteolin (Lut), a flavonoid compound, exerts therapeutic effects against infectious diseases, yet its detailed involvement in fluid homeostasis during pulmonary edema remains unclear. PURPOSE: This study investigated the effects of Lut against pulmonary edema induced by Omicron infection, and elucidated the associated molecular mechanisms. METHODS: An Omicron S pseudovirus infected mouse model was established to evaluate the protective effect of Lut. Lung injury indices were examined using H&E staining, AFC, lung W/D ratio, lung index, total water content, respectively. DARTS-LC-MS/MS, CETSA, molecular docking, Co-IP, and cell-cell fusion were performed to detect the Lut-angiotensin-converting enzyme 2 (ACE2) interaction, while ACE2 and ENaC functions were analyzed by combining their respective siRNA knockdown assays. RESULTS: Pulmonary edema was confirmed under Omicron infection, which was alleviated by Lut dose-dependently, a candidate monomer of traditional Chinese medicine. By directly binding to and downregulating the selected target gene ACE2, Lut suppressed viral entry into host cells. Network pharmacology identified ENaC as a key regulator in pulmonary edema pathogenesis. Mechanistically, the negative regulation between ENaC and ACE2 was weakened by Lut, which exhibited the efficacy against pulmonary edema through ENaC upregulation, thus improving the damaged airway surface liquid height and short-circuit current during Omicron infection. CONCLUSION: Lut ameliorated Omicron-induced pulmonary edema by targeting ACE2 to restore ENaC-mediated sodium transport balance, offering a novel therapeutic strategy for treating COVID-19 related respiratory disorders.