Molecular Mechanisms of Natural Saponins in Treating Acute Lung Injury: Systemic Regulatory Roles Involving Multiple Cell Types and Signaling Pathways.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions characterized by severe pulmonary dysfunction, with persistently high global incidence and mortality. Although glucocorticoids, the standard pharmacotherapy for ALI/ARDS, have been reported to reduce short-term mortality and improve outcomes, their clinical benefit is limited by dose- and duration-dependent adverse effects, thereby driving the exploration of complementary or alternative approaches. Natural saponins, a structurally diverse group of glycosides widely distributed in medicinal plants, have gained considerable interest owing to their multitarget anti-inflammatory, antioxidant, and antiapoptotic activities demonstrated in various in vitro and in vivo ALI models. Here, we systematically review the protective mechanisms of natural saponins from the perspectives of cellular regulation and signaling pathways, highlighting their modulatory effects on macrophages, neutrophils, and other effector cells, as well as their actions through key pathways related to inflammation, oxidative stress, and apoptosis. We further discuss current strategies to overcome the major translational barriers of saponins, particularly structural modifications and formulation approaches aimed at improving oral bioavailability and reducing hemolytic activity. This review consolidates the pharmacological basis for saponin-based ALI therapy and provides a forward-looking perspective on addressing their limitations to facilitate clinical translation.