Sanleng-Ezhu Herb-Pair Synergistically Inhibits PI3K-AKT-mTOR Pathway in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive lung disease with limited effective therapies that significantly improve survival. The disease is characterized by irreversible scarring and impaired lung function, driven by complex cellular and molecular mechanisms. Traditional Chinese medicine (TCM) offers potential avenues for novel treatments. The herb-pair Sanleng (SL) and Ezhu (EZ) has been historically used for pulmonary fibrosis, but the precise synergistic mechanisms and their impact on critical pathways like PI3K-Akt signaling in IPF pathogenesis remained largely unexplored, representing a significant gap in understanding their therapeutic potential.

Researchers employed an integrated multi-omics approach, combining single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing with network pharmacology, to identify key pathways and targets in IPF. They then validated these findings in an in vivo bleomycin-induced murine model of IPF. Mice were treated with the Sanleng-Ezhu herb-pair (combination therapy) or either herb alone (monotherapy). Primary endpoints included assessment of lung histopathological architecture, inflammatory infiltration, and fibrotic remodeling. The study also investigated the impact of treatments on the PI3K-AKT-mTOR signaling pathway to elucidate mechanistic insights.

Integrated scRNA-seq analysis pinpointed IPF-associated epithelial cells (IPF-Epi) as critical contributors to disease pathogenesis, showing significant enrichment in the PI3K-Akt signaling pathway. Subsequent bulk RNA sequencing and network pharmacology identified 13 potential therapeutic targets for SL-EZ, with the PI3K-Akt pathway ranking as the top enriched signaling cascade. In the bleomycin-induced murine model of IPF, the SL-EZ herb-pair markedly improved lung histopathological architecture, significantly attenuated inflammatory infiltration, and alleviated fibrotic remodeling. Mechanistically, this therapeutic efficacy was strongly associated with the suppression of the hyperactivated PI3K-AKT-mTOR signaling pathway. Notably, the combination therapy with SL-EZ demonstrated superior protective effects compared to either monotherapy, underscoring a potent synergistic interaction between the two herbs. This suggests that the combined action of SL-EZ more effectively modulates the disease processes.

The Sanleng-Ezhu combination therapy exerted superior protective effects against IPF compared to either herb administered as monotherapy, highlighting a significant synergistic interaction.