EVA1A-Mediated Signaling Networks in Physiological and Pathological Contexts: Dual Roles in Autophagy and Apoptosis

Eva-1 homolog A (EVA1A) is a transmembrane protein localized on the endoplasmic reticulum and lysosomes. As a key regulator of autophagy and apoptosis, EVA1A regulates neurogenesis, cardioprotection, tumor suppression, and metabolic homeostasis. In this review, we synthesize the multifaceted signaling networks through which EVA1A modulates physiological and pathological processes. These include the PI3K/AKT/mTOR axis (governing neural stem cell maintenance and hepatocellular carcinoma drug resistance), LKB1/AMPK/mTOR pathway (mediating mitochondrial quality control in cardiac injury), mTOR/RPS6KB1 signaling (suppressing glioblastoma proliferation via autophagy-apoptosis crosstalk), and the Hippo-YAP/TAZ cascade (influencing epithelial-mesenchymal transition in thyroid cancer). Crucially, EVA1A exhibits context-dependent dual roles: promoting autophagic flux for homeostasis or triggering apoptosis under stress. Most of these findings are derived from preclinical studies using cell lines and animal models, with limited validation in human tissues or clinical cohorts.We emphasize EVA1A paradoxical effects in cancers, where EVA1A acts as either a tumor suppressor or a modulator of therapy resistance, depending on the tissue-specific microenvironment. Furthermore, EVA1A’s involvement in neurodegenerative and metabolic diseases, such as Alzheimer’s, Parkinson’s, obesity, and diabetes, remains underexplored, despite its relevance to autophagy and inflammation. Understanding the spatiotemporal dynamics of EVA1A interactions with autophagy-related complexes (such as ATG16L1/ATG5/ATG12) and stress-responsive pathways is important to explore its therapeutic potential. However, EVA1A-targeted therapy is still in the early discovery phase, with no current clinical applications.Future studies should focus on the molecular crosstalk between EVA1A-mediated autophagy and metabolic/inflammatory pathways, aiming to facilitate EVA1A-targeted therapeutic development.