Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos

• DOI: 10.1038/s41419-025-07686-x
• Publication Date: 2025-05-19T15:50:04Z
• Authors: Beatriz Villarejo...; Juan Zapata-Muñoz; Elena Sierra-Filardi; Ignacio Ramírez-P...; Lambert Montava-G...; Ian G. Ganley; Patricia Boya

Abstract Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death is key to developing effective, mutation-independent treatments to prevent vision loss. Mitophagy is a protective pathway that prevents age-dependent vision loss and is upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed to investigate the ability of DFP to protect against retinal degeneration via mitophagy. First, we treated mitophagy reporter mice with MNU, a classic inducer of photoreceptor degeneration. MNU induced retinal degeneration and comprehensively inhibited mitophagy, while also inducing lysosomal basification and lysosomal membrane permeabilization. Although DFP rescued cells and retinal explants from the toxic effects of MNU, this effect was independent of mitophagy. Further investigation revealed that PAR polymers accumulation associated with parthanatos cell death was reduced to similar extents by DFP and the PARP inhibitor olaparib. In conclusion, iron chelation can protect against MNU-induced photoreceptor degeneration in retinal explants via parthanatos inhibition.