Abstract Rationale Eosinophils play a pivotal role in the pathogenesis of asthma, yet the mechanisms governing their survival and death remain unclear. SLC7A11, a cystine/glutamate antiporter that maintains redox homeostasis, has recently been implicated in disulfidptosis—a newly identified form of disulfide stress-induced cell death. We observed an increase in SLC7A11 expression in eosinophils during allergic airway inflammation and hypothesized that this upregulation may sensitize eosinophils to disulfidptosis, thereby influencing airway inflammation. Methods A house dust mite (HDM)-induced asthma model was established in wild-type mice. Bronchoalveolar lavage fluid (BALF) was collected, and SLC7A11 expression in eosinophils was assessed by immunofluorescence (IF). Primary eosinophils were isolated and stimulated with interleukin-33 (IL-33) in vitro to evaluate SLC7A11 expression by IF and Western blotting (WB). Based on literature suggesting a link between SLC7A11 and disulfide stress, we used the glucose transporter inhibitor BAY876 to mimic a glucose-limited state. Cell death was quantified by propidium iodide (PI) staining, and disulfidptosis-related indicators—including the NADP+/NADPH ratio, intracellular cystine levels, and disulfide accumulation in cytoskeletal proteins—were analyzed. Results SLC7A11 expression in BALF eosinophils was markedly increased in HDM-induced asthmatic mice. IL-33 stimulation further enhanced SLC7A11 expression in primary eosinophils. Following BAY876 treatment, eosinophils exhibited a significant rise in PI-positive cell death, along with an increased NADP+/NADPH ratio and elevated intracellular cystine levels. Disulfide accumulation in cytoskeletal proteins indicated activation of disulfidptosis. In vivo administration of BAY876 attenuated HDM-induced airway inflammation, suggesting that glucose restriction cooperates with SLC7A11 upregulation to promote disulfidptosis, thereby mitigating airway inflammation. Conclusions Our findings indicate that SLC7A11 upregulation in eosinophils promotes susceptibility to disulfidptosis, which may serve as a regulatory mechanism in allergic airway inflammation. These results reveal a novel SLC7A11-disulfidptosis axis that could represent a potential therapeutic target for asthma. This abstract is funded by: None
Lou et al. (Fri,) studied this question.