A Ginkgo biloba-derived tRNA-derived fragment attenuates asthma by restoring airway structural cell homeostasis via...

Airway remodeling is a critical driver of asthma progression and therapeutic resistance; however, treatment strategies that directly target and reverse this process are still lacking. There is growing evidence that tRNA-derived fragments (tRFs) sourced from Traditional Chinese Medicine (TCM) can modulate disease-associated genes and exert therapeutic effects. We specifically focused on Ginkgo biloba (G. biloba) because of its documented use in traditional practices for respiratory ailments and the reported lung-protective activities of its key bioactive components, such as ginkgolides and flavonoids. Yet, the function of G. biloba-derived tRFs in chronic respiratory conditions like asthma remains elusive, presenting a significant knowledge gap.

This study aimed to investigate the therapeutic potential of tRFs from G. biloba in asthma and to elucidate their underlying mechanisms of action.

Key targets involved in airway remodeling were systematically identified and mapped to G. biloba-derived tRFs. Functional validation was subsequently performed using both asthmatic mouse models and airway structural cells.

We employed an integrated approach combining multi-sample sequencing, bioinformatics analysis, and experimental validation to identify central mediators of airway remodeling and to pinpoint a core G. biloba-derived tRF. The therapeutic efficacy and mechanistic basis of this tRF were further evaluated in house dust mite (HDM)-induced asthmatic mice, as well as in transforming growth factor beta 1 (TGF-β1)-stimulated bronchial epithelial cells (BECs) and airway smooth muscle cells (ASMCs), with or without tRF treatment.

Integrated analysis of human clinical samples, public transcriptomic datasets, and an original TCM RNA database identified prostate transmembrane protein, androgen induced 1 (PMEPA1) as a critical regulator of airway remodeling. PMEPA1 was found to exacerbate mitochondrial dysfunction and dysregulate mitophagy in BECs and ASMCs, thereby promoting their transition to pathological phenotypes and perpetuating chronic airway inflammation. A specific G. biloba-derived tRNA fragment, NO.6-tRF-5-1 (abbreviated as tRF_G6), was identified as a potent regulator of PMEPA1. Treatment with tRF_G6 mimics effectively suppressed PMEPA1 expression, which in turn alleviated airway remodeling and inflammation. By attenuating mitochondrial damage and preventing pathological phenotype shifts in airway structural cells, tRF_G6 disrupts the self-sustaining cycle of airway remodeling in asthma.

Our study reveals that a G. biloba-derived tRNA fragment attenuates asthma by targeting PMEPA1 and restoring mitochondrial function, thereby inhibiting airway remodeling. These results pinpoint PMEPA1 as a novel target and underscore the therapeutic potential of specifically targeting it with G. biloba-derived nucleic acids.