Editorial: Heme Physiology and Pathology

Elena Di Pierro^1*Tiago L Duarte^2*

• ¹Medicine and Metabolic Diseases, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital, Milan, Italy
• ²Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Heme's physiological role as an oxygen carrier is revisited in Dalne et al. ("Evolution of the Oxyhemoglobin Dissociation Curve in . The study quantifies changes in hemoglobin-oxygen affinity (corrected P50) in patients with COVID-19 acute respiratory distress syndrome (ARDS) compared with non-COVID ARDS controls. At ICU admission, COVID-19 ARDS patients exhibited a left-shifted dissociation curve-indicatiing higher oxygen affinity-which remained largely stable over the first three days and was not associated with mortality. These data clarify controversies about altered oxygen binding in COVID-19 and suggest that, despite profound hypoxemia, intrinsic hemoglobin function remains preserved. The findings refine our understanding of oxygen transport physiology under severe inflammatory stress. In the study "Alteration in the Number, Morphology, Function, and Metabolism of Erythrocytes in High-Altitude Polycythemia," Yu et al. use a hypobaric hypoxia rat model to characterize the adaptive and maladaptive responses of erythrocytes under chronic hypoxia. They report increased erythropoiesis and reduced erythrocyte apoptosis, resulting in marked erythrocytosis. Morphological abnormalities (acanthocytes, vesiculated cells) and elevated osmotic fragility indicate membrane instability. Metabolically, erythrocytes upregulate the CD73, adenosine, S1P, and 2,3-BPG pathways, reducing hemoglobin oxygen affinity to facilitate tissue oxygen unloading. These findings reveal how red cells remodel their structure and metabolism to optimize oxygen delivery at altitude, while also predisposing to viscosity-related complications. This Research Topic, Heme Physiology and Pathology, presents six contributions covering the spectrum from molecular mechanisms of heme handling to clinical and pathophysiological implications in different diseases, including liver injury, sickle cell disease, thalassemia, high-altitude polycythemia, and COVID-19-related ARDS. Collectively, these papers highlight the dynamic roles of heme and hemoglobin in health and disease, and point toward novel diagnostic and therapeutic strategies targeting heme metabolism and signaling. The editors hope that this Research Topic will stimulate continued exploration into the physiological and pathological aspects of heme, ultimately advancing therapeutic innovation in red cell and systemic disorders.