Complementary Roles and Synergy of the Ephedra-Glycyrrhiza Herb Pair Across Murine Models of Respiratory Symptoms and Poly(I:C)-Induced Pneumonia

Background The Ephedrae herba (Eh)-Glycyrrhizae Radix et Rhizoma(Grr) herb pair (EGP) is used for viral respiratory illness, but its advantage over single herbs and mechanistic basis remain unclear. Purpose To define the complementary roles and synergistic mechanisms of Eh and Grr within EGP and to assess short-term oral tolerability. Methods Anti-inflammatory, antipyretic, antitussive, and expectorant effects of Eh, Grr, and EGP were evaluated in four corresponding murine models, and synergy was quantified with the Bliss independence model. Single-cell RNA sequencing and bioinformatics were used to implicate relevant cell types and pathways. Key findings were confirmed in Poly(I:C)-stimulated RAW 264.7 cells and lung tissue by ELISA, qPCR, Western blotting, and immunofluorescence. A 7-day oral study evaluated general condition, body weight, serum chemistry, organ indices, and histology. Results EGP improved fever, cough, sputum clearance, and pulmonary inflammation. Antitussive/expectorant effects were predominantly associated with Grr, antipyretic effects mainly with Eh, and both herbs contributed to anti-inflammatory activity. The combination showed synergistic anti-inflammatory effects, with greater interleukin-1β (IL-1β) suppression than either herb alone. p38 MAPK and NF-κB p65 phosphorylation was reduced, and co-inhibition of p38 MAPK and NF-κB ameliorated lung-injury indices and systemic cytokines beyond single inhibitors. No overt toxicity was observed under the 7-day oral dosing conditions at the tested doses. Conclusions EGP shows complementary roles in symptom control—Grr providing antitussive and expectorant effects and Eh antipyretic activity—and synergistic anti-inflammatory action centred on IL-1β, with good short-term oral tolerability in mice.