Panax notoginseng saponins suppress the PI3K/AKT pathway to enhance autophagy and apoptosis in pulmonary fibrosis.

The progressive development of pulmonary fibrosis (PF) is accompanied by an exaggerated inflammatory response and the accumulation of extracellular matrix in the lung parenchyma. Panax notoginseng saponins (PNS) exert promising anti-fibrotic effects involving a cross-talk between autophagy and apoptosis. However, the mechanisms underlying the effects of PNS are yet to be elucidated. In this study, PNS significantly reduced inflammatory injury and collagen deposition in the lungs of PF mice, simultaneously increasing the expression of autophagy-associated and pro-apoptotic genes and the number of autophagosomes and apoptotic bodies. Notably, when either autophagy or apoptosis was inhibited, collagen accumulation was observed. This suggests that both cellular processes independently contribute to the therapeutic effects of PNS. Additionally, while autophagy blockade disruption apoptosis activation, autophagy function remained independent of apoptosis. Network pharmacology and molecular docking analyses showed the PI3K-AKT signal pathway mediating efficacy. The targets included HSP90AA1, MAPK1, STAT3, EGFR, and HIF1A. Furthermore, PNS suppressed the PI3K-AKT signal pathway to modulate autophagy and apoptosis both in vivo and in vitro. Collectively, our findings demonstrate that PNS is a putative therapeutic option in PF that acts via the PI3K-AKT signaling pathway to modulate autophagy and apoptosis. Targeting the cellular degradation machinery is a viable therapeutic strategy for PF.