071 | Decoding eryptosis: human red blood cells response to xenobiotic-induced stress

Marilena Briglia¹, Alice Foti¹, Fabio Allia¹, Rosalia Battaglia¹, Giuseppe Piccione², Alessandro Attanzio³, Caterina Faggio⁴, Roberta Malaguarnera¹, Adriana Carol Eleonora Graziano¹ | ¹Department of Medicine and Surgery, University of Enna “Kore”, Enna, Italy; ²Department of Veterinary Sciences, University of Messina, Messina, Italy; ³Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Italy; ⁴Department of Chemical, Biological, Pharmaceutical and Environmental Sciences ChiBioFarAm, University of Messina, Italy.

Eryptosis is the programmed death of human red blood cells and shares several key features with apoptosis of nucleated cells. This physiological process plays an important role in maintaining erythrocyte homeostasis by ensuring the timely removal of damaged cells, thereby preventing intravascular haemolysis and the release of free haemoglobin into the circulation. However, excessive or dysregulated eryptosis may contribute to the development of anaemia and negatively affect microvascular function. Elevated levels of eryptosis have been described in several pathological conditions, including diabetes mellitus, chronic kidney disease, haemolytic uraemic syndrome, sickle cell disease, thalassemia, and glucose-6-phosphate dehydrogenase deficiency [1]. Despite its clear clinical relevance, the intracellular signaling pathways responsible for the regulation of eryptosis are not yet fully understood. We explored the molecular mechanisms underlying eryptosis using in vitro models of human erythrocytes exposed to selected xenobiotics. Our results show that specific compounds can induce eryptosis by triggering a series of coordinated molecular events, such as increased calcium entry, activation of caspases and non-selective cation channels, ceramide formation, and modulation of kinase-mediated signaling pathways. Among these, Janus-activated kinase 3, AMP-activated protein kinase, casein kinase 1α, and p38 MAP kinase appeared to play a prominent role. Taken together, these findings support the view of eryptosis as an active and finely regulated cell death process that may be susceptible to pharmacological modulation. Further investigation of the signaling pathways and clinically relevant consequences of erythrocyte death may open new perspectives for therapeutic strategies.