JTE-013 ameliorates allergic asthma by targeting the S1PR2-HDAC3-p53 signaling axis to improve mitochondrial homeostasis.

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.