Abstract
BACKGROUND: Pulmonary fibrosis (PF) is a chronic lung disease characterized by ongoing interstitial scarring. Current treatments can only slow the progression of the disease. Resveratrol (RES), a natural polyphenolic compound, has become a potential therapy for PF because of its multiple biological effects, including anti-fibrotic, anti-inflammatory, and antioxidant properties. OBJECTIVES: To clarify RES's efficacy, safety, and mechanism of action in treating PF through a preclinical systematic review. METHODS: A computerized search of eight databases (up to 6 March 2025) was conducted to identify in vivo animal experiments on RES treatment for PF. The SYRCLE tool was used to assess the risk of bias, and meta-analysis was performed using RevMan 5.4 and Stata 17.0. The outcome measures included two main aspects: core pathological processes and molecular mechanisms. Heterogeneity was assessed with the I (2) test, and publication bias was evaluated using funnel plots and Egger's test. RESULTS: A total of 25 studies were included, involving 628 animals in the experimental groups and 357 animals in the control groups. Meta-analysis of selected outcome measures showed: 1. Improved fibrosis: significant reduction in pulmonary fibrosis score (SMD = -2.30, 95% CI [-2.80, -1.79], p < 0.00001, I (2) = 76%) and decreased Hyp content (SMD = -2.16, 95% CI [-2.69, -1.63], p < 0.00001, I (2) = 85%); 2. Inhibited inflammation: reduced TNF-α content (SMD = -1.58, 95% CI [-2.18, -0.99], p < 0.00001, I (2) = 70%) and decreased IL-6 content (SMD = -2.16, 95% CI [-2.74, -1.59], p = 0.007, I (2) = 57%); 3. Restored oxidative balance: decreased MDA content (SMD = -2.22, 95% CI [-3.09, -1.35], p = 0.06, I (2) = 55%) and increased SOD content (SMD = 1.67, 95% CI [1.05, 2.30], p < 0.0001, I (2) = 76%). CONCLUSION: RES significantly enhances the pathological process in PF animal models by regulating the TGF-β/Smad and NF-κB pathways. Future efforts should focus on optimizing preclinical study designs to decrease heterogeneity and improve clinical translation. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/, Identifier CRD420251009847.