Cuproptosis-mediated metabolic-inflammatory coupling in hypertensive myocardial injury: Mechanistic insights and therapeutic perspectives.

Cuproptosis is a recently proposed form of mitochondrial metabolism-dependent cell death, primarily associated with dysregulation of copper ion homeostasis, aggregation of lipoylated tricarboxylic acid cycle proteins, downregulation of iron-sulfur cluster proteins, and mitochondrial proteotoxic stress. Mitochondrial injury serves as an important common pathological basis linking the regulation of cuproptosis to the progression of hypertensive myocardial injury, manifesting as impaired mitochondrial respiratory chain, insufficient ATP production, increased mitochondrial ROS, imbalance in mitochondrial quality control, and disruption of metabolic homeostasis. Existing cardiovascular disease models suggest certain associations between abnormal cuproptosis-related molecules, copper homeostasis imbalance, mitochondrial injury, oxidative stress, and inflammatory responses; however, the direct causal role of cuproptosis in hypertensive myocardial injury remains unclear. Hypertensive myocardial injury involves a continuous interplay of metabolic disorders, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation. Current research suggests that cuproptosis may be one of the candidate stress processes within this pathological network, potentially related to mitochondrial metabolic abnormalities, amplification of oxidative stress, and activation of inflammatory signals. Furthermore, under certain conditions, it may participate in cardiomyocyte injury, fibrosis, and myocardial remodeling. Therefore, at this stage, cuproptosis should not be regarded as a confirmed upstream driver of hypertensive myocardial injury but is more appropriately positioned as a candidate mechanistic node potentially involved in the interaction of metabolic remodeling, mitochondrial injury, and inflammatory amplification. Based on this, this article summarizes the characteristics of metabolic abnormalities and inflammatory responses in hypertensive myocardial injury, reviews the molecular mechanisms of cuproptosis and its research progress in myocardial pathological models, and proposes a mechanistic hypothesis that "cuproptosis may be involved in the metabolic-inflammatory coupling." This article also summarizes exploratory evidence on the regulation of copper homeostasis, mitochondrial-targeted antioxidant strategies, and interventions targeting cuproptosis-related molecules, emphasizing that current research remains primarily based on in vitro experiments, animal models, and bioinformatic analysis, highlighting the need for further validation using human hypertensive myocardial injury samples and prospective studies.