Updated project metadata. Severe malaria (SM) is a life-threatening condition caused by Plasmodium falciparum and the most severe presentation is cerebral malaria (CM) mostly affecting children under five years old. The comprehensive understanding of the complex mechanisms driving the pathophysiology of CM, which encompasses both host and parasite factors, remains insufficiently elucidated. This study analyzed clinical isolates from Beninese children using liquid chromatography-mass spectrometry to identify differentially expressed proteins in SM compared to uncomplicated malaria (UM) patients. We showed a down-regulation of proteins involved in ubiquitination and proteasomal protein degradation in infected erythrocytes from CM patients. In plasma we observed that proteasome 20S components were more abundant in SM patients, which could potentially be useful as a severity biomarker. Furthermore, transferrin receptor protein 1 was specifically upregulated in CM infected erythrocyte isolates which raises the hypothesis that parasites causing CM could preferably infect reticulocytes or erythroid precursors. Consistently with this hypothesis we also found that parasite proteins implicated in distinct biosynthesis pathways were upregulated in CM. Moreover, functional analysis showed deregulated iron metabolism and ferroptosis pathways associated with CM presentation. Further investigations are required to confirm these findings and determine their potential for clinical application.