Resveratrol (RESV) is a naturally occurring polyphenol with well-established antioxidant and anti-inflammatory properties, supporting its therapeutic potential in chronic respiratory diseases such as asthma. To enhance its efficacy, we developed a hybrid compound, R-TBZ, in which RESV is chemically linked to 4-hydroxythiobenzamide (TBZ), a slow-releasing hydrogen sulfide (H₂S) donor. This design aimed to improve chemical stability, bioavailability, and controlled activation while minimizing the toxicity associated with fast H₂S release. R-TBZ was synthesized via esterification of RESV with TBZ and showed high chemical stability, remaining over 95% intact after 24hours under neutral and acidic conditions. Enzymatic hydrolysis occurred gradually (t₁/₂ ≈ 20hours), releasing RESV as the sole detectable product. In allergen-challenged bronchial epithelial cells, R-TBZ demonstrated superior efficacy compared with RESV or TBZ alone. It enhanced mitochondrial antioxidant defenses, reduced mucus production, and suppressed pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). R-TBZ inhibited allergen-induced epithelial-mesenchymal transition and TGF-β-induced fibroblast activation, reducing α-SMA and vimentin expression more effectively than the parent compounds, indicating synergistic anti-remodeling activity. In a murine model of allergic asthma, R-TBZ improved lung function, reduced airway hyperresponsiveness, restored β₂-agonist responsiveness, and attenuated eosinophilic inflammation, Th2 cytokine production, and plasma IgE levels. Importantly, R-TBZ reversed airway structural remodeling, reducing peribronchial α-SMA expression and preserving epithelial and goblet cell morphology, effects not fully achieved by RESV alone. Overall, R-TBZ combines dual anti-inflammatory and anti-remodeling activities, overcoming key limitations of RESV and H₂S donors. This hybrid represents a promising multi-target therapeutic strategy for asthma, particularly for steroid-resistant airway remodeling.
