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Driven by rapid socioeconomic progress and changing lifestyles, the global burden of cardiovascular diseases (CVDs) continues to escalate, with surging morbidity and mortality rates imposing a severe threat to public health. Clinical treatments are focused on the alleviation of treatments, highlighting the need for a deeper understanding of CVDs pathogenesis and the development of targeted therapies. Recent studies have identified imbalances in intracellular Ca²⁺ homeostasis as a key pathological mechanism in the progression of CVDs. Notably, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2), a membrane protein encoded by the ATP2A2 gene and ranging from 97 to 115 kDa in molecular weight, plays a pivotal role in regulating intracellular Ca²⁺ levels. Extensive evidence links abnormal SERCA2 function to various CVDs, including heart failure, cardiac hypertrophy, atherosclerosis, and diabetic cardiomyopathy. This review systematically explores the regulatory mechanisms of SERCA2 expression and its functional regulation-including transcriptional regulation, post-translational modifications, and protein-protein interactions-and further investigates its pathological roles in cardiovascular diseases as well as its potential as a therapeutic target. By synthesizing current knowledge, this article aims to provide new insights for future basic research and establish a theoretical foundation for clinical applications.