Triptolide exerts antiviral effects and alleviates influenza A‑induced pneumonia by inhibiting the overactivation of absent in melanoma 2 signaling in immune cells

Influenza A (H1N1) virus‑induced pneumonia poses a significant clinical challenge because of excessive immune activation and limited targeted therapies. While current antivirals suppress viral replication, they fail to control absent in melanoma 2 (AIM2) inflammasome‑mediated hyperinflammation, a key driver of immunopathology and mortality. The present study investigated whether triptolide (TP) ameliorates H1N1‑induced pneumonia by targeting this unmet need. The results demonstrated that H1N1 infection reduced the levels of inflammatory cytokines in both human bronchial epithelial cells (HBEpiCs) and THP‑1 cells and decreased the adhesion between the two cell types. Furthermore, high‑dose H1N1 activation triggered the AIM2 signaling pathway in THP‑1 cells but not in HBEpiCs and decreased the viability of THP‑1 cells. In vitro and in vivo experiments both confirmed that TP effectively inhibited inflammation in alveolar epithelial cells and immune cells, as well as the adhesion between these cell types. Additionally, TP reduced the viral load of H1N1 in a murine pneumonia model. Further studies revealed that TP inactivated the AIM2 signaling pathway in THP‑1 cells but not in HBEpiCs. However, overexpression of AIM2 in THP‑1 cells markedly reversed the anti‑inflammatory effects of TP. Based on these findings, it was hypothesized that TP modulates the immune response by inactivating the AIM2 signaling pathway in immune cells, which reduces excessive immune cell activation and decreases the harmful interactions between immune cells and alveolar epithelial cells, ultimately alleviating the lung inflammation induced by H1N1 virus infection. The present study proposed a novel mechanism by which TP alleviates lung damage by suppressing AIM2‑driven immune hyperactivation in immune cells, thereby reducing harmful crosstalk with epithelial cells. This is the first evidence of AIM2‑targeted therapy positioning TP as a promising candidate for treating viral pneumonia.