Therapeutic induction of Nrf2 activation to reduce senescence in COPD

Background Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a disease of accelerated lung aging, characterized by oxidative stress, persistent inflammation, and accumulation of senescent cells. Impaired activity of the antioxidant regulator nuclear factor erythroid 2–related factor 2 (Nrf2) contributes to redox imbalance in COPD; however, whether pharmacological activation of Nrf2 can directly modulate senescence-associated processes in COPD remains unclear. Methods We first analyzed senescence markers in lung tissue from COPD patients across GOLD stages. We then investigated the effects of pharmacological Nrf2 activation using obacunone, omaveloxolone, and the reference compound bardoxolone, with metformin as a senescence-modulating comparator, in primary human bronchial epithelial cells (HBECs) from control subjects and COPD patients exposed to cigarette smoke extract (CSE). Senescence hallmarks, including oxidative stress, DNA damage, cell-cycle arrest, and SASP mediators, were assessed. Translational relevance was further evaluated in a murine model of acute lung injury–induced senescence. Results COPD lung tissue exhibited increased DNA damage, altered senescence markers, and telomere shortening, which correlated with disease severity. In HBECs, CSE induced oxidative stress, Nrf2 activation, DNA damage, senescence markers, and SASP factor release, with more pronounced effects in COPD-derived cells. Pharmacological Nrf2 activators significantly enhanced antioxidant defenses, reduced γH2AX accumulation, attenuated senescence markers (p21, p16, SA-β-gal), and suppressed IL-1β and IL-6 secretion in both control and COPD HBECs. Obacunone showed the most consistent protective profile. These effects were recapitulated in vivo, where Nrf2 activation mitigated inflammation, tissue remodeling, and senescence-associated alterations. Conclusions This study demonstrates that pharmacological activation of Nrf2 restores senescence-associated alterations in both healthy and COPD airway epithelial cells and in an in vivo model of lung injury–induced senescence. These findings identify Nrf2 activation, particularly via obacunone, as a promising strategy to target senescence-driven lung pathology.