Tracheloside attenuates pulmonary fibrosis via AMPK-NOX4 signaling
Preclinical models link AMPK activation to reduced oxidative stress and myofibroblast differentiation
image: TCL activates AMPK, which then competitively binds to p22 phox, preventing NOX4 activation. This results in decreased NOX4 expression and promotion of antio-xidant enzyme upregulation, alleviating oxidative stress in myofibroblasts. In the matrix stiffness model, TCL reduces oxidative stress, promoting YAP1 phosphorylation, inhibiting YAP1 nuclear translocation, and facilitating YAP1 degradation. In the TGF-β model, the downregulation of oxidative stress induced by TCL mitigates the transcription of profibrotic genes in the Smad pathway.
Credit: Chinese Journal of Natural Medicines
Idiopathic pulmonary fibrosis (IPF) is a progressive form of pulmonary fibrosis marked by excessive extracellular matrix deposition and irreversible loss of lung function, and current therapies primarily slow, rather than reverse, disease progression.
In a study published in the Chinese Journal of Natural Medicines, researchers investigated the anti-fibrotic activity of tracheloside (TCL) and delineated AMP-activated protein kinase (AMPK) as a key upstream regulator of its effects. Using a bleomycin (BLM)-induced pulmonary fibrosis mouse model, the authors report that TCL reduced fibrotic remodeling in vivo, consistent with suppression of pathogenic tissue scarring in this preclinical setting. To interrogate cellular mechanisms, the team employed complementary in vitro paradigms that recapitulate pro-fibrotic cues: transforming growth factor-β (TGF-β)-driven activation and matrix stiffness–induced myofibroblast differentiation. Across these models, TCL increased AMPK activation and attenuated the acquisition of myofibroblast features associated with extracellular matrix production, supporting a direct inhibitory effect on fibroblast pro-fibrotic programming.
Mechanistic analyses converged on redox signaling as a central node. The study reports that TCL suppressed expression of NADPH oxidase 4 (NOX4), increased antioxidant enzyme expression, and reduced oxidative stress in the tested systems. NOX4 is a major enzymatic source of reactive oxygen species in fibrotic microenvironments and has been implicated in sustaining fibroblast activation and matrix accumulation; therefore, downregulation of NOX4 provides a plausible biochemical route by which TCL limits pro-fibrotic signaling output. Importantly, the authors position AMPK upstream of NOX4 regulation. They report that AMPK activation inhibited NOX4 expression and further restrained NOX4 activation through a proposed competitive interaction involving p22^phox, a component associated with NADPH oxidase complex function. Collectively, these data support an AMPK/NOX4 signaling axis linking TCL exposure to reduced oxidative stress and diminished myofibroblast differentiation, two processes that contribute to fibrotic progression in experimental models.
While the findings are based on animal and cell-based systems and therefore require further validation for clinical translation, the study provides mechanistic evidence that AMPK-dependent suppression of NOX4-associated oxidative stress may underlie tracheloside’s anti-fibrotic activity, highlighting a potentially actionable pathway in pulmonary fibrosis research.
Full article available at: https://www.sciencedirect.com/science/article/abs/pii/S1875536425000251