Emerging role of SIRT1 in asthma and COPD from molecular mechanisms to translational therapy.

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory disorders with distinct pathological mechanisms. Even advancements in conventional therapies, the treatment of these diseases remains challenging due to their complex pathophysiology and limited efficacy of current anti-inflammatory treatments. SIRT1, an NAD+-dependent deacetylase, exerting protective effects by inhibiting NF-κB and STAT3, activating Nrf2 and FOXO3, and suppressing TGF-β/Smad. In asthma, SIRT1 attenuates Th2 inflammation, mucus hypersecretion, and airway smooth muscle proliferation; in COPD, it reduces neutrophilic inflammation, alveolar senescence, and protease/antiprotease imbalance. Shared benefits include mitigation of oxidative stress, mitochondrial dysfunction, and extracellular matrix remodeling. However, clinical translation faces critical barriers: cell type-specific SIRT1 effects, pharmacokinetic limitations of current activators, and lack of biomarker-guided strategies. This review examines challenges, compares SIRT1's divergent roles, and evaluates chronotherapy, biomarker-guided selection, and SIRT1 activators. Integration of current evidence and knowledge gaps reveals pathways to personalized SIRT1-targeted therapies for obstructive airway diseases.

Key Findings

• SIRT1 activates Nrf2 and FOXO3, contributing to protective effects against oxidative stress in asthma and COPD.
• SIRT1 attenuates inflammation, mucus hypersecretion, and airway smooth muscle proliferation in asthma, and reduces neutrophilic inflammation and alveolar senescence in COPD.
• Clinical translation of SIRT1 activators is challenged by cell type-specific effects, pharmacokinetic limitations, and lack of biomarker-guided strategies.

Clinical Significance

Citation

Wasim Muhammad, Parveen Rabia, Chen Rilinget al.. Emerging role of SIRT1 in asthma and COPD from molecular mechanisms to translational therapy. iScience. 2026-Jun-19.