Combined effects of extreme heat and NO2 on liver disease progression of T2DM mice.

Extreme hot temperature and heavy traffic pollution are increasingly prevalent environmental stressors and are independently associated with adverse metabolic outcomes, but their combined effects on metabolically-associated liver disease (MASLD) in type 2 diabetes mellitus (T2DM) remain unclear. This study employed a T2DM mouse model exposed to 4 h of daily extreme heat at 40°C and nitrogen dioxide with 5 ppm during six weeks in order to assess their interaction in relation to MASLD development. Results showed that combined exposure raised blood glucose levels and aggravated hepatic histopathological damage in T2DM mice. Combined exposure increased lipid peroxidation, as indicated by elevated oxidative stress markers (MDA), while antioxidant markers (CAT, SOD, GSH-PX) were reduced. Inflammatory factors (TNF-α, IL-1β, IL-6, and NF-κB) were significantly upregulated, and immune balance was disrupted (IL-4/IFN-γ ratio). Intestinal permeability increased, with alterations in gut microbiota composition. Mechanistically, these changes were associated with impaired hepatic autophagy, endoplasmic reticulum stress, and ferroptosis-related pathways, leading to accelerated MASLD progression. Capsazepine (CZP) alleviated liver injury by reducing inflammation, oxidative stress, and restoring cellular pathways. This study provides a potential strategy for early prevention and management of MASLD in T2DM.