HERPUD1 is a multifunctional endoplasmic reticulum (ER) protein that plays crucial roles in cellular stress responses and disease pathogenesis. The protein primarily functions in ER quality control and stress adaptation, with its expression regulated by the Nrf1 transcription factor through antioxidant response elements in its promoter 1. HERPUD1 governs mitochondrial function by regulating inositol 1,4,5-trisphosphate receptor (ITPR3)-mediated calcium signaling, controlling intracellular Ca2+ release and mitochondrial Ca2+ influx 2. In disease contexts, HERPUD1 demonstrates complex roles across different pathologies. In cardiovascular disease, it promotes homocysteine-induced aortic valve calcification through ER stress pathways, with deficiency alleviating calcification by activating autophagy 3. Conversely, in cancer, HERPUD1 promotes tumor cell survival and aggressiveness by sustaining autophagy and inhibiting apoptosis via PI3K/AKT/mTOR and p38 MAPK signaling pathways 4. The protein's stability is regulated by CK2 kinase through Ser-59 phosphorylation 5. In neurological contexts, HERPUD1 appears protective, with increased expression correlating with neuronal survival after intracerebral hemorrhage 6. These findings establish HERPUD1 as a context-dependent regulator of cellular survival and death, making it a potential therapeutic target across multiple diseases.