The interactive regulation between calcium transients and autophagy serves as a core mechanism for maintaining cellular homeostasis, and dysregulation of this signaling axis contributes to the pathological progression of various human diseases. Although emerging evidence has confirmed the correlation between calcium signaling and autophagy, how the spatiotemporal characteristics of distinct subcellular calcium microdomains specifically modulate autophagic activity and mediate pathological damage remains lacking in systematic mechanistic elucidation and theoretical summary. Based on compartmentalized calcium signaling characteristics of the endoplasmic reticulum, lysosomes, mitochondria, and plasma membrane, this review systematically delineates the core molecular mechanisms underlying autophagy regulation by spatially defined calcium signals, with a focus on the bidirectional patterns of the calcium-autophagy axis in key pathological processes, including programmed cell death, oxidative stress, inflammatory responses, and nutrient deprivation. Furthermore, this study summarizes the pathogenic roles of the calcium-autophagy regulatory axis in cardiovascular disorders, neurological diseases, malignant tumors, and renal diseases, and deeply analyzes the inherent limitations and translational bottlenecks of current broad-spectrum therapeutic strategies targeting general calcium signaling or autophagy. In view of the insufficient precision and contradictory therapeutic outcomes of conventional global modulation, this review highlights innovative strategies for organelle-targeted and spatiotemporally precise intervention. It provides a comprehensive theoretical basis for clarifying the disease-specific functions of the calcium transient-autophagy axis and advancing mechanistic research and precise clinical translation of related diseases.
