Protein Arginine Methyltransferases in γ-Globin Regulation and Sickle Cell Disease: Emerging Connections to Oxidative Stress

Abstract

Reactive oxygen species (ROS) are unavoidable byproducts of cellular metabolism and are normally controlled by tightly regulated antioxidant systems. Red blood cells (RBCs) are particularly susceptible to oxidative stress due to their high oxygen exposure and iron content. In sickle cell disease (SCD), this vulnerability is exacerbated, as sickled RBCs generate chronically elevated ROS that contribute directly to disease pathophysiology. This review examines emerging evidence linking oxidative stress responses to regulation of fetal hemoglobin (HbF) expression through protein arginine methyltransferases (PRMTs). PRMTs catalyze arginine methylation of histone and non-histone substrates, thereby shaping chromatin structure, transcriptional programs, and translational control. We highlight recent findings demonstrating that specific PRMTs regulate γ-globin expression through distinct mechanisms, including transcriptional repression at the β-globin locus and post-transcriptional control of γ-globin mRNA translation. We propose that oxidative stress signaling may modulate PRMT activity, creating a mechanistic link between cellular stress responses and HbF induction. Because HbF inhibits pathological hemoglobin S polymerization, PRMT-dependent pathways represent an attractive therapeutic axis for SCD and related β-hemoglobinopathies. By integrating oxidative stress biology with PRMT-mediated epigenetic and translational regulation, this review outlines a unifying framework for HbF control, identifies critical knowledge gaps, and highlights future directions for the development of targeted epigenetic therapies.

Key findings

• ▸Reactive oxygen species (ROS) are chronically elevated in sickle cell disease and exacerbate RBC vulnerability due to high iron content and oxygen exposure.
• ▸Protein arginine methyltransferases (PRMTs) regulate gamma-globin expression through distinct mechanisms involving chromatin structure shaping and translational control.
• ▸Oxidative stress signaling may directly modulate PRMT activity, establishing a novel mechanistic link between cellular stress responses and the induction of protective fetal hemoglobin.

Keywords

Identifiers

DOI

10.3390/antiox15030324

Journal

Antioxidants

Year

2026