Work

Ginsenoside Rk2 combined with dexamethasone enhances the anti neutrophilic asthma effect via STAT1/NLRP3-NETs-Th17/Treg axis

Year: 2026

Type: article

Abstract: : Background Neutrophilic asthma (NA) is a severe, corticosteroid-resistant phenotype associated with neutrophil extracellular traps (NETs) formation and Th17/Treg imbalance. Cold exposure exacerbates NA progression, increasing the global clinical burden. Currently, combination therapy with corticosteroids is considered a viable approach. This study aimed to investigate the therapeutic potential and mechanisms of ginsenoside Rk2 (Rk2) combined with dexamethasone (DEX) against cold-stimulated neutrophilic asthma (CSNA). Methods A corticosteroid-resistant BEAS-2B cell model was established by NTHi stimulation. A CSNA mouse model was established via ovalbumin sensitization, NTHi infection, and cold stimulation, followed by Rk2 and/or DEX treatment. Airway hyperresponsiveness, histopathology, and neutrophil infiltration were measured to assess therapeutic efficacy. Th17/Treg populations were analyzed by flow cytometry. NETs formation was quantified in PMA-stimulated primary mouse neutrophils. A NETs-naïve CD4+ T cell co-culture system was used to examine the causal role of NETs in Th17/Treg imbalance. Transcriptomics and agonist-based gain-of-function experiments were conducted to validate the mechanism of Rk2 combined with DEX. Results Rk2 reversed DEX resistance by rebalancing GR α /GR β , upregulating HDAC2, and promoting GR α nuclear translocation. Compared with monotherapy, Rk2 combined with DEX ameliorated airway inflammation and restored Th17/Treg homeostasis. Mechanistically, this combination therapy suppressed NETs formation by reducing NETs components, DNA release and ROS generation. NETs drove Th17/Treg imbalance via STAT1/NLRP3 inflammasome axis. Pharmacological activation of either STAT1 or NLRP3 reversed the beneficial effects. Conclusion Our findings demonstrate for the first time that Rk2, a potent natural corticosteroid potentiator, acts in combination with DEX to alleviate CSNA by suppressing the STAT1/NLRP3 inflammasome-NETs-Th17/Treg cascade.

Source: Journal of Ginseng Research

DOI: 10.1016/j.jgr.2026.101116