Abstract: Objective To explore the clinical features, systematic diagnostic process, and iron chelation therapy strategies of secondary iron overload in aceruloplasminemia (ACP). Methods A retrospective analysis was performed on the clinical data of patients diagnosed with aceruloplasminemia in Peking Union Medical College Hospital from December 2018 to September 2025. The clinical manifestations related to iron overload, key diagnostic points, and treatment responses were systematically summarized. Results A total of four patients were diagnosed with ACP. All of them had middle to late onset of the disease, and all had diabetes. Among them, 3 cases presented with progressive neurological symptoms. All patients showed a characteristic pattern of abnormal iron metabolism:significantly elevated serum ferritin (range:730-12 091 ng/mL), decreased transferrin saturation (range:4. 9%-23. 4%), and significantly reduced or undetectable ceruloplasmin levels. Genetic testing confirmed pathogenic mutations in the CP gene in all patients. For diagnosis, it is necessary to take the clinical "triad" (diabetes mellitus, neurological symptoms, anemia) as clues, combine with characteristic abnormalities in iron metabolism indicators and imaging evidence, and conduct differentiation from other iron overload diseases such as hereditary hemochromatosis. In terms of treatment, all the 4 patients received iron chelation therapy, including deferoxamine, deferiprone, and deferasirox. One of the patients showed a significant decrease in serum ferritin level with improvement in neurological symptoms after treatment. Conclusions Iron overload secondary to ACP has insidious manifestations, and its clinical diagnosis relies on a high degree of vigilance and systematic iron metabolism evaluation. Establishing a stepwise diagnostic process from clinical screening to genetic testing is crucial. Early initiation and implementation of individualized iron chelation therapy is a core therapeutic measure to effectively manage iron overload and delay the progression of multiple organ damage.