# Sex-Dependent Metabolic Alterations in Red Blood Cells During COVID-19

## TL;DR

The study reveals that red blood cells undergo significant metabolic changes during COVID-19, with differences observed between men and women, suggesting a new perspective on disease progression and biomarker potential.

## Contribution

The study identifies sex-dependent metabolic alterations in red blood cells during COVID-19, highlighting their role in disease pathology and biomarker development.

## Key findings

- Red blood cells show metabolic changes in energy balance, redox homeostasis, and amino acid handling during COVID-19.
- Men exhibit broader metabolic perturbations in red blood cells, especially in severe disease, compared to women.
- Comorbidities like diabetes and obesity influence red blood cell metabolic patterns in COVID-19.

## Abstract

Although it is well known that COVID-19 affects red blood cells, the specific metabolic alterations and their relationship to disease outcome have not been fully explored. This study aimed to investigate how COVID-19 alters red blood cell metabolism and whether these changes differ according to sex, disease severity, and major risk factors. Our results show that COVID-19 is associated with significant alterations in red blood cell metabolism, involving pathways related to energy balance, redox homeostasis, and amino acid handling. These changes likely reflect the systemic metabolic stress induced by infection, including hypoxia, inflammation, and oxidative burden. Notably, we observed differences between men and women, with men exhibiting a broader extent of metabolic perturbations, particularly in severe disease. Comorbidities such as diabetes, obesity, and cardiovascular disease further shaped these metabolic patterns, underscoring the integrative role of red blood cells as indicators of systemic pathophysiological states. By highlighting red blood cells as active participants in disease progression rather than passive oxygen carriers, this work identifies a previously underappreciated layer of COVID-19 pathology and underscores the potential of red blood cell metabolism as a source of biomarkers.

COVID-19 is known to impair red blood cell (RBC) function, which may affect oxygen transport and disease progression. However, the metabolic consequences of SARS-CoV-2 infection on RBCs and how these changes relate to disease severity and sex differences, have not been systematically explored. Here, we compared RBC metabolomic profiles from healthy controls and individuals with COVID-19 using nuclear magnetic resonance (NMR) to gain insight into disease mechanisms and potential biomarkers. Multivariate and univariate analyses were performed within the men and women cohorts, and clinical factors, including body mass index, comorbidities, and critical clinical status were considered. We found that COVID-19 induces significant metabolic remodeling in RBCs of all patients, including reduced glycolytic and pentose phosphate pathway (PPP) intermediates, consistent with impaired energetic and antioxidant capacity. However, we also observed differences between men and women in the pattern and extent of these changes. Female patients showed changes in metabolites implicated in oxygen release and amino sugar metabolism, including 2,3-BPG, suggesting a distinct metabolic adaptation. By contrast, male patients exhibited a broader set of RBC-specific metabolic disruptions, most evident in severe disease, characterized by decreased amino acid levels, altered glycolytic activity, and weakened antioxidant responses. Overall, these findings identify RBC metabolism as a component of COVID-19 pathophysiology and support its potential as a source of biomarkers.