Atp2a3, which encodes the sarco(endo)plasmic reticulum Ca2+-ATPase 3 (SERCA3), is crucial for maintaining intracellular Ca2+ homeostasis by pumping Ca2+ into the endoplasmic reticulum. This function is fundamental for various cellular processes, such as cell growth, apoptosis, and intracellular signaling pathways [6,7,8,9].

In primary aldosteronism, machine learning identified Atp2a3 as a key feature gene in aldosterone-producing adenomas (APAs). Silencing Atp2a3 in human adrenocortical cells decreased basal CYP11B2 expression and aldosterone secretion, indicating its role in regulating aldosterone production [1]. In breast cancer cell lines, resveratrol up-regulated Atp2a3 expression through epigenetic mechanisms, which was related to apoptosis and changes in intracellular Ca2+ management [2,6]. In hepatocellular carcinoma cells, histone deacetylase inhibitors increased Atp2a3 expression, and HCC patients with high Atp2a3 expression had longer overall survival [3]. In prostate cancer cells, salinomycin triggered endoplasmic reticulum stress through Atp2a3 upregulation, promoting apoptosis [4]. In type 2 diabetes mellitus-induced cognitive impairment, urolithin A protected neuronal cells by inhibiting Atp2a3 expression, suppressing endoplasmic reticulum stress and Tau hyperphosphorylation [5].

In conclusion, Atp2a3 is essential for intracellular Ca2+ homeostasis and is involved in multiple biological processes and diseases. Studies in different cell models have revealed its role in diseases like primary aldosteronism, cancer, and diabetes-associated cognitive impairment, highlighting its potential as a therapeutic target in these disease areas.