LXR/RXR activation mitigates ferroptosis in diabetic cardiomyocytes by regulating Calpain1 via Calpastatin.

Ferroptosis significantly contributes to myocardial injury in Type 2 Diabetes Mellitus (T2DM). Liver X Receptor (LXR) and Retinoid X Receptor (RXR) play crucial roles in lipid metabolism and inflammation, but their involvement in regulating ferroptosis in diabetic cardiomyocytes is not fully understood. High-fat diet/streptozotocin-induced T2DM mouse models and high glucose and high fat (HG)-exposed cardiomyocytes were used to assess the impact of LXR activation on myocardial injury and ferroptosis. The study also examined the role of the ROS/AMPK/Nrf2 pathway and the effect of LXR/RXR activation on Calpain1 and Calpastatin expression. Activation of LXR was shown to reduce myocardial injury susceptibility by protecting cardiomyocytes from ferroptosis. This protection occurs via relieving HG-induced ROS-mediated suppression of the AMPK/Nrf2 axis, preventing ferroptosis under hyperglycemic conditions. Moreover, pharmacological activation of LXR/RXR heterodimers was found to alleviate cardiomyocyte injury by downregulating Calpain1, a protein that induces ferroptosis through mitochondrial pathways. Mechanistically, LXR/RXR resulted in the transcriptional activation of Calpastatin, which in turn inhibited Calpain1 expression. This inhibition of Calpain1 led to reduction of mitochondrial ROS overproduction, thereby disinhibiting the AMPK/Nrf2 pathway, significantly reducing ferroptosis and myocardial injury. LXR activation protects against T2DM-induced myocardial injury by inhibiting ferroptosis, particularly through the LXR/RXR-Calpastatin-Calpain1 axis, offering a potential therapeutic strategy for T2DM-related heart damage.