Abstract

Objective:This study aimed to investigate the role of endoplasmic reticulum stress (ERS) in atopic dermatitis (AD) and its comorbid mental disorders and evaluate the therapeutic potential of mesencephalic astrocyte-derived neurotrophic factor (MANF).Methods:Clinical samples from patients with AD and comorbidities were analyzed for ERS and apoptosis markers using quantitative polymerase chain reaction and western blotting. Mouse models of depression were developed using 28 days of chronic unpredictable mild stress (CUMS), and dermatitis was induced using 0.2% 2,4-dinitrofluorobenzene. Adenovirus-mediated MANF overexpression was induced via local injection to develop comorbidities, comorbidities + negative control overexpression, and comorbidities + MANF overexpression groups. Further, the ERS inhibitors of 4-phenylbutyric acid were employed for the comorbidities + inhibitors group. Dermatitis scoring, the sucrose preference test for behavioral changes, and ERS and apoptosis assessments using transmission electron microscopy, terminal deoxynucleotidyl transferase dUTP Nick-End labeling staining, hematoxylin and eosin staining, and immunohistochemistry were conducted.Results:Clinical data demonstrated significant increases in ERS-related markers (GRP78, P-IRE1, and Caspase-12) and apoptosis marker of Bax, whereas Bcl-2 was decreased in comorbidities compared with those with AD alone. In mouse models, increased Bax and decreased Bcl-2 indicated apoptotic pathway activation in the comorbidities group. MANF overexpression reduced ERS-related factors and skin pathology while improving behavioral indicators. Further, MANF reduced skin cell apoptosis by downregulating Bax and upregulating Bcl-2. ERS inhibitors similarly alleviated cell apoptosis, thereby confirming the critical role of ERS in disease progression.Conclusion:MANF overexpression reduces ERS and apoptosis, which improves AD symptoms and comorbid mental disorders, thereby highlighting its therapeutic target pote