Work

SHLP2 alleviates allergic asthma by inhibiting ETV5/GSDMD signaling pathway-mediated pyroptosis

Year: 2025

Type: article

Abstract: BACKGROUND: Allergic asthma (AA) is a lung disease characterized by impaired respiratory function and significant infiltration of inflammatory cells. Human Protein-Mimicking Peptide-2 (SHLP2) is a recently discovered mitochondria-encoded peptide that plays a crucial role in mitochondrial retrograde signaling pathways. However, its potential utility in mitigating AA remains unexplored. Our study investigates the therapeutic potential of SHLP2 in AA. RESULTS: We found that SHLP2 expression was significantly lower in the serum of patients with AA and correlated with key AA biomarkers. Exogenous SHLP2 supplementation alleviated house dust mites (HDM)-induced lung inflammation and airway barrier damage in mice. Additionally, SHLP2 ameliorated mitochondrial damage and inhibited pyroptosis in bronchial epithelial cells. At the mechanistic level, we identified a binding site between SHLP2 and the promoter region of the ETS Variant Transcription Factor 5 (ETV5) using a luciferase reporter assay. SHLP2 inhibited the transcription of downstream GSDMD, thereby suppressing pyroptosis. CONCLUSIONS: Overexpression of ETV5 improved mitochondrial function and reduced pyroptosis in bronchial epithelial cells. However, exogenous SHLP2 supplementation failed to reverse the exacerbation of HDM-induced lung inflammation and airway barrier damage caused by ETV5 knockout in mice. These findings highlight SHLP2 as a key ETV5/GSDMD signaling pathway regulator, inhibiting pyroptosis and mitigating AA progression.

Source: Cellular Signalling

DOI: 10.1016/j.cellsig.2025.112126