Inositol 1,4,5-trisphosphate receptors (IP₃Rs) play a crucial role in maintaining intracellular/cytosolic calcium ion (Ca²⁺_i) homeostasis. The release of Ca²⁺ from IP₃Rs serves as a second messenger and a modulatory factor influencing various intracellular and interorganelle communications during both physiological and pathological processes. Accumulating evidence from in vitro, in vivo, and clinical studies supports the notion that the overactivation of IP₃Rs is linked to the pathogenesis of various cardiac conditions. The overactivation of IP₃Rs results in the dysregulation of Ca²⁺ concentration ([Ca²⁺]) within cytosolic, mitochondrial, and nucleoplasmic cellular compartments. In cardiovascular pathologies, two isoforms of IP₃Rs, i.e., IP₃R1 and IP₃R2, have been identified. Notably, IP₃R1 plays a pivotal role in cardiac ischemia and diabetes-induced arrhythmias, while IP₃R2 is implicated in sepsis-induced cardiomyopathy and cardiac hypertrophy. Furthermore, IP₃Rs have been reported to be involved in various programmed cell death (PCD) pathways, such as apoptosis, pyroptosis, and ferroptosis underscoring their multifaceted roles in cardiac pathophysiology. Based on these findings, it is evident that exploring potential therapeutic avenues becomes crucial. Both genetic ablation and pharmacological intervention using IP₃R antagonists have emerged as promising strategies against IP₃R-related pathologies suggesting their potential therapeutic potency. This review summarizes the roles of IP₃Rs in cardiac physiology and pathology and establishes a foundational understanding with a particular focus on their involvement in the various PCD pathways within the context of cardiovascular diseases.

Ferroptosis is an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation. Emerging evidence indicates that susceptibility to ferroptosis is not governed solely by cytosolic signaling pathways, but instead results from the coordinated actions of multiple intracellular organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), and lipid droplets (LDs). Mitochondria play dual roles in ferroptosis by integrating metabolic activity, redox balance, and mitochondrial quality control; thereby influencing reactive oxygen species (ROS) generation and lipid peroxidation. Lysosomes regulate ferroptotic sensitivity through iron mobilization, inter-organelle iron transfer, lysosomal redox activity/lipid peroxidation, lysosomal signaling hub, and ferritinophagy. The ER contributes to ferroptosis by coordinating lipid biosynthesis, membrane polyunsaturated fatty acid composition, and unfolded protein response signaling, as well as by disrupting antioxidant defenses and iron homeostasis, especially during ER stress. Lipid droplets function as dynamic lipid reservoirs that buffer oxidizable fatty acids or, upon mobilization, supply substrates that fuel ferroptosis-associated lipid peroxidation. Here, we provide a comprehensive review of current mechanistic insights and recent advances in organelle-specific regulation and inter-organelle cross talk during ferroptosis, highlighting emerging therapeutic opportunities and key experimental challenges. An integrated understanding of this multi-organelle regulatory network is essential for modulating ferroptosis in human diseases.

Background: Cognitive impairment is the most frequent mental health problem among people with heart failure (HF). Brain pathologies in HF‐induced cognitive impairment are possibly associated with the imbalance of brain mitochondrial dynamics. Therefore, therapeutic interventions targeting mitochondrial dynamics by mitochondrial fission inhibition or mitochondrial fusion enhancement would provide beneficial outcomes to the brain of HF subjects. This study aimed to test whether modulating mitochondrial dynamic improves cognitive function in HF rats via reduced brain mitochondrial dysfunction, and dendritic spine loss.Method: Rats underwent either sham surgery or permanent left anterior descending coronary artery ligation‐induced myocardial infarction (MI). MI rats developed HF with reduced ejection fraction (%LVEF <50%) at 1‐week post‐operation. Then, MI rats were assigned to receive one of four following interventions: (1) DMSO as a vehicle, (2) enalapril (a positive control, 10 mg/kg/day, orally), (3) mitochondrial division Inhibitor (Mdivi‐1, 1.2 mg/kg/day, intraperitoneal (IP) injection), (4) mitochondrial fusion promotor (M1, 2 mg/kg/day, IP injection). All rats were received the intervention for 4 weeks, then, the cognitive function via NOL was assessed, and were sacrificed. Brain mitochondrial function and dendritic spine density were determined.Result: HF rats developed cognitive impairment, when compared to the sham group, and it was associated with increased brain mitochondrial oxidative stress, and dendritic spine loss in hippocampus (Figure). Treatment with Mdivi‐1 and M1 improved cognitive function similar to enalapril, as indicated by increasing %preference of NOL. Furthermore, all treatments effectively reduced brain mitochondrial ROS levels and hippocampal dendritic spine loss in HF rats (Figure).Conclusion: Mitochondrial fusion inhibitor and mitochondrial fusion improved cognitive function in HF rats through a reduction of mitochondrial ROS levels and preserved dendritic spine density.

Background: Cognitive impairment was frequently found following myocardial infarction (MI). Apoptosis, particularly in the hippocampal area, has been proposed as a mechanism involving in the cognitive impairment through the initiation of brain cell death and subsequently dendritic spine loss. The hypothesis of this study is that the inhibition of apoptosis using a pan‐caspase inhibitor (Z‐VAD‐FMK) improves hippocampal dependent cognitive function in MI rats via attenuating brain apoptosis and dendritic spine lossMethod: Male Wistar rats were divided into sham operation or permanent left anterior descending coronary artery ligation‐induced MI. After one week, MI rats with LVEF less than 50% were randomly assigned to one of three interventions: (1) MI‐vehicle (DMSO), (2) Enalapril as a positive control (10 mg/kg/day, PO), and (3) A pan‐caspase inhibitor (Z‐VAD‐FMK, 1 mg/kg/day, IP). All rats received the intervention for 4 weeks, then cardiac function and hippocampal‐dependent cognitive function were assessed before they were sacrificed. Hippocampal dendritic spine density and apoptotic protein expression were determined.Result: MI‐vehicle rats exhibited cardiac dysfunction (as shown by a decrease in %LVEF), cognitive impairment (as shown by decreased %preference of novel object recognition), and hippocampal dendritic spine loss. Furthermore, our data showed that apoptosis was significantly increased (as shown by increased cleaved‐caspase 3/Pro‐caspase 3 levels) in MI‐vehicle rats, compared with the sham rats (as shown in Figure). Treatment with Z‐VAD‐FMK and enalapril equally improved cardiac function, cognitive function, and increased hippocampal dendritic spine density, compared with the MI‐vehicle rats. Z‐VAD‐FMK demonstrated a greater benefit in reducing apoptosis than enalapril in the brain of MI rats.Conclusion: Apoptosis inhibitor shared similar efficacy with enalapril in improving cognitive function through suppressing brain apoptosis and restoring hippocampal dendritic spine density in MI rats.