Dusquetide Regulates SQSTM1/p62-Mediated Mitophagy to Alleviate PM2.5-Aggravated Airway Inflammation in Asthma.

Objective To investigate the pathological mechanism by which fine particulate matter (PM2.5) exacerbates asthma,with a focus on SQSTM1/p62-mediated mitophagy,and to evaluate the regulatory and therapeutic potential of dusquetide in this process. Methods A house dust mite (HDM)-induced asthma model was established with 6- to 8-week-old female C57BL/6 mice,which were then exposed to PM2.5.Control,HDM,HDM+PM2.5 (HP),and intervention (HP+Mdivi-1 and HP+dusquetide) groups were established.Airway hyperresponsiveness was assessed through whole-body plethysmography,and airway inflammation and mucus secretion were evaluated by HE and PAS staining.Immunofluorescence assay was employed to detect the co-localization of TOMM20 and LC3B.Key factors were screened and validated by LC-MS/MS-based mitochondrial proteomics. Results PM2.5 exposure enhanced airway hyperresponsiveness (P<0.01),exacerbated inflammation and mucus secretion (P<0.01),and increased TOMM20 and LC3B co-localization signals (P<0.01) in HDM-sensitized mice.Mdivi-1 inhibition of mitophagy reduced inflammation (P<0.01).Mitochondrial proteomics identified SQSTM1/p62 as a core regulatory factor,whose expression was up-regulated after PM2.5 exposure (P<0.01).Dusquetide intervention inhibited SQSTM1/p62 function and mitophagy (P<0.01),reduced airway hyperresponsiveness in mice of the HP group (P<0.01),and alleviated inflammatory manifestations (P<0.01). Conclusion PM2.5 exacerbates HDM-induced asthma pathology by activating SQSTM1/p62-mediated mitophagy,while dusquetide effectively alleviates this process,demonstrating the potential as a therapeutic target for PM2.5-related asthma.