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JTE-013 ameliorates allergic asthma by targeting the S1PR2-HDAC3-p53 signaling axis to improve mitochondrial
Simiao Xu1, Kun Guo1, Ningpo Ding1
1Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, Jilin, China.
Background:
Asthma, driven by epithelial mitochondrial dysfunction, lacks effective treatments. JTE-013, a selective sphingosine-1-phosphate receptor 2 (S1PR2) antagonist, has unknown mechanisms in asthma.
Objective:
We aimed to evaluate the efficacy of JTE-013 in ovalbumin (OVA)-induced asthmatic mice and elucidate its underlying mechanism, hypothesizing that it may restore mitochondrial homeostasis via the S1PR2-HDAC3-p53 pathway.
Methods:
We established an in vivo model of OVA-induced mice and an in vitro model of BEAS-2B cells subjected to house dust mite (HDM) treatment. We applied pharmacological and genetic interventions targeting S1PR2, HDAC3, and p53, followed by Western blotting, immunofluorescence (IF), co-immunoprecipitation (Co-IP), flow cytometry, and ROS/MMP quantitative assays.
Results:
In the animal model, JTE-013 significantly alleviated airway inflammation, mucus hypersecretion, and remodeling. At the cellular level, JTE-013 exerted protective effects against HDM-driven damage in BEAS-2B cells by alleviating oxidative stress (restoring Nrf2/HO-1), preventing mitochondrial dysfunction (stabilizing MMP, inhibiting DRP1 fission), and inhibiting apoptosis. These protective effects were highly dependent on HDAC3. To validate the S1PR2-HDAC3-p53 axis, we demonstrated that the cytoprotection from S1PR2 knockdown (mimicking JTE-013) was eliminated by siHDAC3, an effect that was subsequently restored by p53 inhibition (Pifithrin-α).
Conclusion:
JTE-013, as an S1PR2 antagonist, potentially modulates HDAC3-mediated p53 deacetylation, mitigating oxidative stress, mitochondrial dysfunction, and apoptosis to ameliorate allergic asthma.
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