Current and Future Landscape of SERCAs' Functions in Non‐Excitatory Cells and Diseases

Abstract Calcium (Ca 2+ ) signaling as the primary intracellular second messenger orchestrates a myriad of physiological processes. Maintaining Ca 2+ homeostasis relies on Ca 2+ channels, pumps, exchangers, and buffers. Sarco/endoplasmic reticulum Ca 2+ ‐ATPases (SERCAs or ATP2A) encoded by ATP2A1 , ATP2A2 , or ATP2A3 are primary Ca 2+ pumps localized on the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) that actively sequester Ca 2+ from the cytoplasm back to the ER/SR, thereby preventing the detrimental overload of cytoplasmic Ca 2+ concentration. Recent studies have highlighted the significant roles and the underlying mechanisms of SERCAs in non‐excitatory cells such as those within epithelial, adipose, immune, and reproductive systems or tissues. This article aims to provide a comprehensive summary of the functional characteristics and regulatory mechanisms of the SERCA family, with a particular focus on the latest research concerning their roles and mechanisms in various non‐excitatory cells and related cancers. This work will provide insight into understanding the Ca 2+ signaling regulatory networks mediated by SERCAs and their implications for the diagnosis and treatment of Ca 2+ dyshomeostasis‐related diseases and propose potentially constructive suggestions for the direction of research around Ca 2+ signaling transductions, as well as guiding strategies for disease diagnosis, treatment, and drug development by targeting SERCAs.