Inhibition of ABCG2 prevents phototoxicity in a mouse model of erythropoietic protoporphyria

Junjie Zhu, Fu-Ying Qin, Saifei Lei, Ruizhi Gu, Qian Qi, Jie Lu, Karl E. Anderson, Peter Wipf and Xiaochao Ma ()
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Junjie Zhu: University of Pittsburgh
Fu-Ying Qin: University of Pittsburgh
Saifei Lei: University of Pittsburgh
Ruizhi Gu: University of Pittsburgh
Qian Qi: University of Pittsburgh
Jie Lu: University of Pittsburgh
Karl E. Anderson: University of Texas Medical Branch
Peter Wipf: University of Pittsburgh
Xiaochao Ma: University of Pittsburgh

Nature Communications, 2024, vol. 15, issue 1, 1-8

Abstract: Abstract Erythropoietic protoporphyria (EPP) is a genetic disease characterized by protoporphyrin IX-mediated painful phototoxicity. Currently, options for the management of EPP-associated phototoxicity are limited and no oral medication is available. Here, we investigated a novel therapy against EPP-associated phototoxicity by targeting the ATP-binding cassette subfamily G member 2 (ABCG2), the efflux transporter of protoporphyrin IX. Oral ABCG2 inhibitors were developed, and they successfully prevented EPP-associated phototoxicity in a genetically engineered EPP mouse model. Mechanistically, ABCG2 inhibitors suppress protoporphyrin IX release from erythroid cells and reduce the systemic exposure to protoporphyrin IX in EPP. In summary, our work establishes a novel strategy for EPP therapy by targeting ABCG2 and provides oral ABCG2 inhibitors that can effectively prevent protoporphyrin IX-mediated phototoxicity in mice.

Date: 2024
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DOI: 10.1038/s41467-024-54969-6

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