Glucocorticoid (GC) resistance in chronic obstructive pulmonary disease (COPD) induced by long-term smoking, significantly reduces the quality of life of patients. The complex interaction between antioxidants and acetylation is an important factor that contributes to the slow progression of treatment. This study highlights the development of GC resistance in COPD through 4-hydroxynonenal (4-HNE), multidrug resistance-associated protein 1 (MRP1), histone deacetylase 2 (HDAC2), and nuclear related factor 2 (Nrf2), using enzyme-linked immunosorbent assays, western blotting, and siRNA silencing. Our results suggest that long-term exposure to cigarette smoke can increase 4-HNE toxicity via reactive oxygen species (ROS)-induced lipid peroxidation and decrease the expression of MRP1, histone HDAC2, and Nrf2. Together, these molecules form and enhance the cyclic resistance pathway in COPD, including MRP1 reducing 4-HNE efflux, 4-HNE down-regulating HDAC2 expression by oxidation, HDAC2 reducing Nrf2 transcription by deacetylation, and Nrf2 reducing MRP1 expression through acetylation. The HuaTanJiangQi Capsule (HTJQ) reduces GC resistance via a triple regulatory pathway by enhancing the activity of HDAC2, promoting the transcription of Nrf2, up-regulating the expression of MRP1, and reducing lipid peroxidation induced by ROS. Thus, this cyclic mechanism of GC resistance in COPD may open new avenues for robust therapies using HTJQ.