Calcium homeostasis imbalance in sepsis: molecular mechanisms and therapeutic perspectives

Calcium ions (Ca²⁺) are pleiotropic signaling messengers that regulate diverse cellular processes, and their homeostasis is essential for normal physiology at cellular, tissue, and organismal levels. Accumulating evidence identifies Ca²⁺ dysregulation as a key driver of sepsis onset and progression. In this review, we systematically delineate the mechanisms governing intracellular Ca²⁺ homeostasis, focusing on coordinated regulation among the endoplasmic reticulum, mitochondria, and lysosomes. We also discuss the molecular basis of disordered Ca²⁺ signaling in sepsis-associated pathologies and summarize recent therapeutic strategies targeting Ca²⁺ homeostasis, together with their translational prospects and challenges. Unlike prior reviews focusing on single organelles or individual organs, this review provides an integrative framework for organellar Ca²⁺ communication in sepsis. We propose that inflammatory insults progressively disrupt coordinated inter-organellar Ca²⁺ exchange, switching physiological coupling toward pathological states. Such aberrant inter-organellar crosstalk initiates a self-amplifying vicious cycle that ultimately propagates cellular injury to systemic multi-organ failure. Collectively, further exploration of dynamic organellar interplay within the Ca²⁺ regulatory network may yield new mechanistic insights and facilitate precise therapeutic strategies for sepsis.