Ingenol ameliorates silicosis via targeting the PTGS2/PI3K/AKT signaling axis: Implications for therapeutic intervention

Silicosis, formerly known as silico, is an irreversible disease caused by prolonged inhalation of substantial amounts of free crystalline silica dust, characterized by pulmonary inflammation and extensive nodular fibrosis. The etiology of the disease remains unclear, which currently hinders the development of effective therapeutic drugs and interventions. Ingenol (Ing), a terpenoid active ingredient found in plants of the Euphorbiaceae family, including the entire herb of Euphorbia helioscopia, Euphorbia kansui, or Euphorbia lathyris, demonstrates significant anti-inflammatory and antiviral activities. In this study, we identified and confirmed that Ingenol can significantly ameliorate silicosis induced by silica dioxide by inhibiting the PTGS2/PI3K/AKT signaling pathway. In vivo, Ingenol improves pulmonary respiratory function and reduces inflammation and fibrosis in a murine model of CS-induced silicosis. In vitro, Ingenol inhibits the expression of cellular factors associated with inflammation and fibrosis, as well as macrophage apoptosis and fibroblast migration. Furthermore, it can modulate the expression of fibrosis-related proteins, thereby inhibiting CS-induced fibrotic responses. Mechanistically, a combination of bioinformatics, network pharmacology, and experimental validation indicates that Ingenol mitigates the progression of silicosis by modulating the PTGS2/PI3K/AKT signaling pathway. In summary, these findings suggest that Ingenol is a potential candidate for the treatment of silicosis.