Figure 4.

Potential molecular mechanisms of SGLT2 inhibitors on oxidative stress, endoplasmic reticulum stress, inflammation factors, and fibrosis in diabetic cardiomyopathy. SGLT2Is can inhibit oxidative stress by rising levels of free Zn²⁺ in cardiomyocytes, translocation of Nrf2 to the cell nucleus, activation of the Nrf2–ARE signal, and activation of the sGC–cGMP–PKG pathway. SGLT2Is also inhibit ERS through inhibition of CHOP and GRP78. Inflammation factors, such as NLRP3, ASC, caspase 1, IL6, TNFα, and MCP1, are all attenuated by SGLT2Is dependent of AMPK activation. SGLT2Is prevent cardiac fibrosis through the SGK1–ENac and TGFβ–Smad pathways. All these changes by SGLT2Is lead to attenuation of cardiomyocyte apoptosis, hypertrophy, and fibrosis.