Novel porphyrin photosensitizer LD4-PDT alleviates asthma airway remodeling by inhibiting EGR1-dependent TGF-β1/Smad signaling

Asthma, a common chronic inflammatory airway disease, affects 300 million people globally. Pathologically, it features Th2/Th17-driven airway inflammation and remodeling, which worsens disease and impairs lung function. Current therapies alleviate symptoms but cannot prevent irreversible airway structural changes, highlighting the need for targeted treatments. The TGF-β1/Smad axis is pivotal for epithelial‒mesenchymal transition (EMT) and airway fibrosis‒key features of asthmatic remodeling. This study aimed to explore the interaction between the TGF-β1/Smad pathway and EGR1 and evaluate the effect of LD4-based photodynamic therapy (LD4-PDT) as a potential anti-inflammatory agent on asthma by evaluating inflammatory cell infiltration, nitrosative and oxidative stress markers, and EMT-related substances in a rat model of asthma. Primarily, we evaluated the efficacy of LD4-PDT in ovalbumin (OVA)-induced asthmatic rats. Assessments included pulmonary function (FVC, MMF), airway histopathology, oxidative stress markers, and EMT-related proteins (TGF-β1, Smad, MMP-9). Transcriptomics identified key targets, molecular docking verified binding, and TGF-β1-stimulated BEAS-2B/16HBE cells validated mechanisms in vitro. LD4-PDT exerted dose-dependent effects: improved lung function (increased FVC/MMF), reduced inflammation (lower IgE/TNF-α), and attenuated remodeling (decreased collagen deposition and PAS+ cells). Mechanistically, it suppressed EMT by inhibiting EGR1-dependent TGF-β1/Smad signaling and modulating arachidonic acid metabolism. Transcriptomics confirmed EGR1 as a critical mediator, and molecular docking showed strong LD4-EGR1 binding-providing a molecular basis for LD4-PDT's effects. LD4-PDT effectively targets EGR1-driven EMT, inflammation, and metabolic dysregulation, emerging as a novel therapeutic strategy for asthma.