Cardiovascular diseases remain the leading cause of global mortality, with atherosclerosis representing their most prevalent pathological substrate. While inflammation, lipid dysregulation, endothelial dysfunction, and mitochondrial injury are well-recognized contributors, emerging evidence has identified a novel form of regulated cell death known as cuproptosis as a central mechanistic axis linking metabolic dysregulation, mitochondrial stress, and vascular pathology. Cuproptosis is triggered by intracellular copper accumulation that directly targets lipoylated enzymes of the tricarboxylic acid cycle, inducing toxic protein aggregation, proteotoxic stress, and collapse of mitochondrial bioenergetics. Recent studies have expanded the relevance of this process from cancer biology to cardiovascular disorders, including diabetic myocardial injury and atherosclerosis, where copper dysregulation and mitochondrial vulnerability converge to drive tissue damage and maladaptive remodeling (Yang et al., 2023; Huo et al., 2023).

Simultaneously, advances in RNA biology have uncovered complex regulatory networks centered on RNA-binding proteins such as U2AF2 and mitochondrial proteins such as complement C1q binding protein (C1QBP, also known as p32), which coordinate gene expression, metabolic reprogramming, and stress responses. U2AF2, a core spliceosomal factor, has been shown to integrate long non-coding RNA signaling with metabolic and oncogenic pathways, including lipid metabolism and mitochondrial function, while C1QBP is now recognized as a critical regulator of mitochondrial translation, oxidative phosphorylation, and TCA cycle integrity in both cardiac and cancer contexts (Wang et al., 2022; Tian et al., 2024; Wang et al., 2022).

This study synthesizes evidence from molecular pharmacology, cardiovascular biology, RNA splicing research, and copper metabolism to propose an integrated pathogenic model in which dysregulated copper trafficking, aberrant cuproptotic signaling, and RNA-binding regulatory circuits converge to drive atherosclerosis and cardiac dysfunction. By integrating cuproptosis-specific gene signatures identified in human atherosclerotic tissue (Chen et al., 2023; Cui et al., 2023) with mitochondrial copper signaling pathways (Huo et al., 2023; Miner et al., 2019) and U2AF2-dependent RNA regulatory loops (Wang et al., 2022; Jiang et al., 2020), this article establishes a coherent mechanistic framework explaining how metabolic stress translates into vascular injury and plaque instability. The analysis further explores how lncRNAs such as ZFAS1 and NEAT1 reprogram RNA stability and splicing in copper-stressed cells, amplifying inflammatory and metabolic derangements (Wang et al., 2022; Liu et al., 2025).

Beyond theoretical integration, this work highlights novel diagnostic and therapeutic opportunities. Cuproptosis-related gene signatures provide a robust molecular fingerprint of atherosclerotic activity, while targeting copper transporters, mitochondrial chaperones, and RNA-binding proteins may enable precise modulation of vascular cell survival and metabolism. By reframing cardiovascular disease as a disorder of mitochondrial copper-dependent proteostasis governed by RNA-regulatory networks, this article offers a transformative perspective that unifies metabolic, genetic, and inflammatory paradigms into a single, actionable pathophysiological model.

Cuproptosis, Atherosclerosis, Mitochondria

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