Fig. 7
Schematic diagram. Hyperglycemia induced by STZ leads to reduced expression and activity of SERCA2, resulting in impaired calcium uptake into the ER and disruption of calcium homeostasis, particularly within ER stores. This calcium imbalance elicits ER stress and activates stress response pathways such as the IRE1α signaling cascade. Persistent ER stress promotes cell death, evidenced by increased expression of CHOP and Bax together with cleavage of caspase-3 and caspase-12. These molecular alterations contribute to the development of depression-like behaviors. Treatment with TUDCA attenuates ER stress, thereby reducing cell death and ameliorating depression-like phenotypes. Pharmacological activation of SERCA2 by CDN1163 restores ER calcium regulation, which in turn alleviates ER stress, suppresses cell death, and improves behavioral outcomes.
