Bu-fei decoction ameliorates naïve CD4⁺ T cell senescence and attenuates age-related COPD by regulating the...

cGAS-STING-induced cellular senescence is a key driver of age-related chronic obstructive pulmonary disease (COPD). Bu-fei decoction (BFD) is a traditional Chinese medicine formula with significant clinical efficacy for COPD. However, the specific mechanism by which BFD modulates the cGAS-STING pathway to impact age-related COPD remains unclear.

To evaluate the therapeutic efficacy of BFD in age-related COPD and elucidate the underlying mechanisms.

Flow cytometry and RT-qPCR were conducted to assess the phenotypes and transcriptional profiles of peripheral CD4⁺ naïve T cells from aged COPD patients and healthy controls. Young and aged COPD mouse models were established using cigarette smoke extract and lipopolysaccharide to investigate age-dependent mechanisms and BFD-related effects. C1qbp-knockdown Jurkat T cells were used to validate BFD's mechanisms in vitro. Network pharmacology and molecular docking predicted BFD-derived bioactive compounds targeting the cGAS-STING pathway.

C1qbp downregulation in CD4⁺ T_naive cells of aged COPD patients and mice significantly correlated with activated cGAS-STING signaling and elevated senescence markers. C1qbp knockdown in Jurkat T cells recapitulated these findings, triggering spontaneous cGAS-STING activation and senescence-related gene upregulation. BFD exhibited multi-therapeutic effects in aged COPD mice, improving lung function, reducing pulmonary inflammation, and restoring CD4⁺ T_naive populations while suppressing cGAS-STING signaling and cellular senescence. The therapeutic benefits were substantially diminished when C1qbp was silenced. Twelve potential cGAS-STING-targeting bioactive compounds were predicted from BFD, mainly including formononetin, β-sitosterol, quercetin, etc. CONCLUSION: BFD mitigates CD4⁺ T_naive cell senescence and attenuates age-related COPD, primarily by inhibiting the cGAS-STING pathway in a C1qbp-dependent manner.