Mitochondrion-targeted antioxidant SS-31 blocks cuproptosis to reduce airway remodeling in chronic asthma

Airway remodeling is a critical and difficult-to-control aspect of chronic asthma, contributing significantly to its progression. While various forms of cell death are known to influence asthma development, the role of cuproptosis—a novel copper-dependent cell death mechanism—particularly in bronchial epithelial cells, remains largely unexplored. Understanding this pathway could uncover new therapeutic targets, as current standard-of-care treatments often fail to fully address the underlying remodeling processes that lead to persistent symptoms and lung function decline.

Researchers established a mouse model of chronic asthma using repetitive OVA exposure. They also simulated airway remodeling in vitro by incubating human bronchial epithelial BEAS-2B cells with recombinant human IL-4 and TGF-β1. In the mouse model, they investigated the effects of a cuproptosis blocker, the mitochondrion-targeted antioxidant Szeto-Schiller (SS)-31, on airway remodeling markers. Primary endpoints included Cu2+ levels, expression of cuproptosis-related genes, airway responsiveness, lung inflammation, subepithelial fibrosis, mucus hypersecretion, and EMT-related protein expression.

In chronic asthmatic mice, cuproptosis significantly increased following repetitive OVA exposure, evidenced by elevated Cu2+ levels in bronchoalveolar lavage fluid (BALF) and increased protein expression of cuproptosis-related genes (FDX-1, LIAS, and DLAT). This was accompanied by increased airway responsiveness, lung inflammation, greater area of subepithelial fibrosis, and mucus hypersecretion. Furthermore, expression of EMT-related proteins (MMP-2, MMP-9, N-cadherin, vimentin, and α-SMA) was also elevated. Importantly, treatment with the cuproptosis blocker, SS-31, substantially inhibited all these observed processes. Partial colocalization of FDX-1 and the bronchial epithelial marker Keratin 8/18 suggested OVA mediates remodeling via bronchial epithelial cuproptosis. > In vitro, rhIL-4 and TGF-β1 mediation in BEAS-2B cells similarly increased cuproptosis, indicated by elevated Cu2+ levels in supernatant and cytoplasm, and increased protein expression of FDX-1, LIAS, and DLAT.