Eryptosis in Acute Patients: A Hypothesis on Its Potential Clinical Impact and Current Gaps in Evidence

Abstract

Sepsis is a life-threatening condition driven by a dysregulated host response to infection and remains a leading cause of mortality and morbidity worldwide. Among the many mechanisms implicated in its pathophysiology, the contribution of eryptosis—programmed red blood cell (RBC) death—has been suggested but remains insufficiently investigated. In this hypothesis paper, we propose that eryptosis may represent an underrecognized driver of sepsis-induced anemia and a potential contributor to subsequent organ dysfunction. This hypothesis is supported only by fragmented, predominantly preclinical evidence, which is currently too limited to allow firm conclusions. In this context, we critically revisit the sparse data linking sepsis, endotoxemia, and eryptosis, and outline a testable framework for understanding their possible interaction. We emphasize the substantial gaps in current knowledge, including the absence of robust clinical studies, the heterogeneity of existing experimental models, and persistent uncertainty regarding causality versus mere association. We also explore the theoretical implications of modulating eryptosis as a potential therapeutic approach. Our aim is to stimulate scientific discussion and promote targeted research efforts that may help determine whether addressing eryptosis could ultimately contribute to mitigating anemia, reducing organ injury, and improving outcomes in critically ill patients affected by sepsis.