Dihydromyricetin alleviates lipid peroxidation-induced Pyroptosis by inhibiting xCT ubiquitination and degradation in experimental COPD model

Background: Dihydromyricetin (DHM), a flavonoid primarily sourced from Ampelopsis grossedentata, exhibits anti-inflammatory and antioxidant biological activities. However, the therapeutic effects and the precise underlying mechanism of DHM in chronic obstructive pulmonary disease (COPD) are poorly understood.

Purpose: Our study aimed to investigate the effects of DHM on COPD and the underlying mechanism.

Methods: In vitro, Beas-2b cells were treated with cigarette smoke extract (CSE) for 24 h. In vivo, BALB/c mice were exposed to cigarette smoke (CS)/ lipopolysaccharide (LPS) for 4 weeks to establish mouse models of COPD.

Results: DHM reversed the decreased cell viability, lipid peroxidation, and the downregulated expression of xCT and GPx4 in CSE-treated cells. Moreover, DHM suppressed the CSE-induced GSDMD-mediated Pyroptosis activated by the NLPR3 inflammasome and the nonclassical caspase-4 inflammasome. Moreover, DHM improved membrane destruction, mitochondrial damage and pyrogenic corpuscle formation caused by CSE. However, xCT knockdown strongly attenuated the inhibitory effects of DHM on CSE-induced cell death, lipid peroxidation and Pyroptosis. Furthermore, we demonstrated that DHM protected against CSE-induced Pyroptosis by inhibiting lipid peroxidation triggered by ubiquitination-mediated xCT degradation. In vivo experiments demonstrated that DHM significantly attenuated inflammatory cells infiltration and pro-inflammatory factors secretion in BALF of COPD mice, relieved airway wall thickening and alveolar structural damage, concurrently reducing airway resistance while suppressing lipid peroxidation and Pyroptosis in lung tissues of COPD mice. However, conditional knockdown of xCT in mouse lung epithelial cells abolished the protective effects of DHM against COPD, as evidenced by the failure to attenuate inflammatory cell infiltration and cytokine secretion in BALF, to alleviate pathological changes such as pulmonary interstitial thickening, and to suppress Pyroptosis pathway activation.

Conclusion: Our findings uncovered a novel therapeutic mechanism of DHM in COPD, demonstrating its ability to mitigate disease progression by targeting xCT-dependent lipid peroxidation and Pyroptosis. This study provides a strong rationale for developing DHM as a clinically viable treatment for COPD.

COPD; Dihydromyricetin; Lipid peroxidation; Pyroptosis; xCT.