用木犀草素靶向ACE2，可改善奥密克戎感染下肺上皮钠转运失衡的情况。

Abstract

Luteolin directly targets ACE2. • Binding to ACE2, Luteolin prevents Omicron invading into host cells. • Luteolin restores ENaC function, alleviating Omicron-induced pulmonary edema. 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 therapeu