HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

Oxidative stress-mediated retinal pigment epithelium (RPE) degeneration plays a vital role in retinal degeneration with irreversible visual impairment, most notably in age-related macular degeneration (AMD), but a key pathogenic factor and the targeted medical control remain controversial and unclear. In this work, by sophisticated high-throughput sequencing and biochemistry investigations, the major pathologic processes during RPE degeneration in the sodium iodate-induced oxidative stress model has been identified to be heme oxygenase-1 (HO-1)-regulated ferroptosis, which is controlled by the Nrf2-SLC7A11-HO-1 hierarchy, through which ferrous ion accumulation and lethal oxidative stress cause RPE death and subsequently photoreceptor degeneration. By direct knockdown of HO-1 or using HO-1 inhibitor ZnPP, the specific inhibition of HO-1 overexpression has been determined to significantly block RPE ferroptosis. In mice, treatment with ZnPP effectively rescued RPE degeneration and achieved superior therapeutic effects: substantial recovery of the retinal structure and visual function. These findings highlight that targeting HO-1-mediated RPE ferroptosis could serve as an effectively retinal-protective strategy for retinal degenerative diseases prevention, including AMD.

Automated summary

Research has identified that oxidative stress-induced RPE degeneration is mainly regulated by HO-1-mediated ferroptosis, controlled by the Nrf2-SLC7A11-HO-1 pathway. In mouse experiments, inhibiting HO-1 can block RPE ferroptosis, and using the HO-1 inhibitor ZnPP effectively rescues RPE degeneration with superior therapeutic effects. This highlights that targeting HO-1-mediated RPE ferroptosis could serve as an effective retinal-protective strategy for preventing retinal degenerative diseases, including AMD.