Alcoholic cardiomyopathy: Metabolic stress, inflammation, epigenetic reprogramming, and therapeutic strategies

Alcoholic cardiomyopathy (ACM) is a major form of non-ischaemic dilated cardiomyopathy characterized by ventricular dilation and impaired systolic function following chronic alcohol exposure. Despite partial reversibility with prolonged abstinence, ACM remains an important cause of cardiovascular morbidity and mortality, while the molecular mechanisms driving disease initiation and progression are incompletely understood. Emerging evidence indicates that ACM is not solely a consequence of direct ethanol toxicity, but rather a complex disorder involving interconnected metabolic, inflammatory, immune, and epigenetic pathways. In this review, we summarize current advances in the pathophysiology of ACM and propose an integrated immunometabolic framework underlying disease progression. Chronic alcohol exposure induces oxidative stress, mitochondrial dysfunction, calcium mishandling, and endoplasmic reticulum stress, leading to cardiomyocyte injury and impaired cellular energetics. These disturbances activate pro-inflammatory signaling pathways, including NF-κB and the NLRP3 inflammasome, promoting cytokine production and inflammatory forms of programmed cell death such as pyroptosis. Concurrently, accumulating evidence implicates immune dysregulation as a central contributor to adverse remodeling, characterized by altered T-cell polarization, macrophage phenotypic switching, and dysregulated immune checkpoint signaling that sustain chronic inflammation and fibrosis. In parallel, alcohol-induced epigenetic and post-transcriptional mechanisms, including DNA methylation, histone modifications, and microRNA-mediated regulation, establish persistent transcriptional reprogramming that links transient metabolic stress to long-term alterations in cardiomyocyte function and myocardial structure. Collectively, these pathways form a self-reinforcing network of metabolic injury, immune activation, and maladaptive remodeling that drives ACM progression. A more integrated understanding of these mechanisms identifies oxidative stress, inflammasome activation, immune imbalance, and epigenetic reprogramming as interconnected and potentially targetable processes. Therapeutic strategies combining alcohol abstinence with mechanism-based interventions targeting these pathways may provide new opportunities for precision treatment of ACM.