Ergothioneine Preserves Splenic Architecture and Attenuates Hepatic Histopathological Alterations in a Humanized Mouse Model of Sickle Cell Anemia
Year: 2026
Type: article
Abstract: Introduction Sickle cell anemia (SCA) is characterized by chronic hemolysis, oxidative stress, inflammation, and recurrent vaso-occlusive events that promote progressive damage in multiple organs. Ergothioneine (ERT) is a naturally occurring thiol antioxidant that accumulates in erythrocytes through the OCTN1 transporter and has cytoprotective properties that may attenuate oxidative tissue injury. However, its effects on chronic histopathological alterations associated with SCA remain poorly understood. This study evaluated the effects of prolonged ERT supplementation on histopathological alterations in the spleen, liver, and kidney of humanized SCA mice. Methods Humanized mice were generated by transplantation of bone marrow mononuclear cells from Berkeley SS or SA donors into lethally irradiated recipients (CEUA/UNICAMP; protocol 5955-1/2022). Experimental groups comprised SA controls, untreated SS mice, and SS mice treated with ERT (35 mg/kg/day, orally, for 60-days; n=5/group). Histopathological evaluation of spleen, liver, and kidney sections was performed using hematoxylin-eosin and Masson's trichrome staining. Tissue organization, perivascular erythrocyte accumulation, fibrosis, megakaryocyte infiltration, hemosiderin deposition, necrosis, and, in the liver, hyperplasia were assessed using a blinded three-point semiquantitative scoring system. Group comparisons were performed using the Kruskal-Wallis test followed by Dunn's multiple-comparison test with Holm correction. Results: ERT selectively modulated histopathological alterations in humanized SCA mice. In the spleen, ERT significantly improved tissue organization (p=0.025 vs. SS) and reduced megakaryocyte infiltration (p=0.011 vs. SS), whereas no significant effects were observed on fibrosis, hemosiderin deposition, or perivascular erythrocyte accumulation. In the liver, ERT significantly reduced perivascular erythrocyte accumulation (p=0.025 vs. SS) and hyperplasia (p=0.003 vs. SS), while hemosiderin deposition remained unchanged. Renal architecture remained preserved across all experimental groups, and ERT did not significantly modify renal perivascular erythrocyte accumulation. Conclusion Collectively, these findings demonstrate that prolonged ERT supplementation selectively attenuated histopathological alterations associated with SCA, predominantly affecting splenic tissue organization and megakaryocyte infiltration, as well as hepatic vascular congestion and hyperplasia. These results support further investigation of ERT as an adjunctive strategy to mitigate chronic organ injury associated with SCA.
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223095064