The Interplay Between Ca²⁺ Homeostasis, Endoplasmic Reticulum Stress, and the Unfolded Protein Response in Human Diseases

Highlights: What are the main findings? The Ca²⁺-ER Stress–UPR is a pivotal, highly sensitive signaling hub that connects Ca²⁺ homeostasis within the ER to protein quality control, cell fate, and a variety of downstream pathophysiological responses. The process is bidirectional with a self-amplifying mechanism, such that the result of Ca²⁺ depletion in the ER, whether attributed to SERCA malfunction, leak channels, or UPR, leads to suppression of PERK-CHOP, a maladaptive component of UPR, which in turn suppresses SERCA, thus entrapping the cell in a Ca²⁺-depleted, pro-apoptotic state. What are the implications of the main findings? The Ca²⁺-ER Stress–UPR system is a common fundamental pathological mechanism that explains several diversified diseases, including neurodegeneration, CVD, and cancer, thus identifying a single, multi-disease target. The targeted therapy should be directed at the modulation of ER Ca²⁺ homeostasis, e.g., via activators of SERCA, or, alternatively, at the pharmacological redirection of the UPR from the maladaptive, CHOP-mediated phase to the adaptive, pro-survival phase. The maintenance of endoplasmic reticulum (ER) Ca²⁺ homeostasis is intrinsically linked to the fidelity of protein folding, forming a functional tether that, when disrupted, triggers the Unfolded Protein Response (UPR). This bidirectional axis serves as a critical rheostat for cellular viability, yet its chronic dysregulation underpins the molecular etiology of numerous pathologies, including neurodegeneration, heart failure, and malignant transformation. This review provides a comprehensive interrogation of the Ca²⁺-ER Stress–UPR network, delineating how primary stress sensors—PERK, IRE1alpha, and ATF6—engage in complex feedback loops that either reinstate equilibrium or commit the cell to apoptosis. We specifically examine the PERK-CHOP-SERCA2b inhibitory circuit as a central driver of persistent Ca²⁺ depletion and discuss the role of Mitochondria-Associated Membranes (MAMs) in governing lethal Ca²⁺ transfer. Notably, we move beyond the classical paradigm of CHOP as a terminal apoptotic executioner, incorporating emerging evidence of its context-dependent adaptive functions. By synthesizing mechanistic insights across diverse disease models, this work highlights the transition from adaptive to maladaptive UPR as a universal pathological checkpoint. Ultimately, we evaluate the therapeutic potential of ‘axis-targeted’ interventions, such as SERCA activators and selective UPR modulators, aimed at resolving the underlying Ca²⁺ signaling defects in ER stress-related disorders.