<p>Chronic obstructive pulmonary disease (COPD) is a prevalent inflammatory disorder with limited treatment options. Photodynamic therapy (PDT) may offer a novel approach due to its reactive oxygen species-mediated mechanism. LD4, a novel porphyrin-based photosensitizer we developed, has demonstrated potent antibacterial, antiseptic, and anti-inflammatory effects in previous studies, including efficacy in pulmonary fibrosis. Here, we report our findings on LD4-based photodynamic therapy (LD4-PDT) for COPD in a rat model, along with its underlying mechanism of action. A rat COPD model was established by exposing rats to cigarette smoke (CS) and bacterial infection over 63 days. LD4-PDT was administered every two days for a total of six treatments. The effects of LD4-PDT on lung function and inflammation were assessed using histological and biochemical methods. Results showed that LD4-PDT significantly improved CS-induced lung function impairment, inhibited inflammatory cell infiltration, and reduced cytokine production. Transcriptomic analysis and validation experiments identified early growth response 1 (EGR1) as a potential target of LD4-PDT, with expression changes consistent with its involvement in the therapy’s effects. At the cellular level, LD4-PDT suppressed cigarette smoke extract-induced EGR1 expression and nuclear translocation. Furthermore, LD4-PDT reversed CS-induced epithelial-mesenchymal transition (EMT), as evidenced by increased E-cadherin expression and decreased levels of Vimentin and Snail. In summary, LD4-PDT attenuated activation of the MAPK pathway (ERK1/2 and JNK). Using pharmacological inhibitors in vitro, we provide evidence that LD4-PDT may modulate EMT and exert anti-inflammatory effects through the EGR1/MAPK axis. These findings suggest that LD4-PDT is a promising potential intervention for alleviating key pathological features of airway-dominant stable COPD.</p>