SIRT6 Attenuates ER Stress‐Associated Mucus Hypersecretion via Regulation of NRF2 in Asthma Models

Persistent exposure to house dust mite (HDM) worsens asthma severity, contributing to long-term morbidity. Histone deacetylase sirtuin 6 (SIRT6) is known to regulate airway inflammation and remodeling in epithelial cells. This study sought to identify the protective effect and potential mechanism of SIRT6 on endoplasmic reticulum (ER) stress-associated mucus hypersecretion in HDM-induced asthma. In this study, we established a house dust mite (HDM)-induced murine asthma model through sensitization and challenge protocols, and then developed an IL-13-stimulated inflammatory model using Beas-2B bronchial epithelial cells. The results revealed that airway epithelial cells from asthmatic mice demonstrated upregulated SIRT6 expression concomitant with increased levels of BIP, CHOP, and MUC5AC. IL-13 stimulation significantly upregulated SIRT6 expression in Beas-2B cells, paralleled by elevated BIP and CHOP levels. SIRT6 overexpression markedly reduced reactive oxygen species (ROS) generation and attenuated the expression of BIP, CHOP, and MUC5AC. Conversely, SIRT6 silencing exacerbated ROS production and enhanced BIP, CHOP, and MUC5AC expression. Furthermore, SIRT6 selectively suppressed ATF6 expression without altering ATF4, XBP-1s, or phospho-eIF2α levels. Mechanistically, SIRT6 increased NRF2 protein expression while reducing its acetylation, resulting in amplified NRF2 signaling. These findings demonstrate that SIRT6 ameliorates ER stress and mucus hypersecretion in airway epithelium via regulation of the NRF2, positioning SIRT6 as a promising therapeutic target for asthma.