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

Abstract

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.

Intraocular iron injection induces oxidative stress followed by elements of geographic atrophy and sympathetic ophthalmia

“…Hiramitsu et al (1976) reported photoreceptor degeneration induced by IVT injections of linoleic acid hydroperoxide in rabbits. Ferroptosis, an irondependent programmed cell death pathway, is accompanied by lipid peroxide accumulation (Yang & Stockwell, 2016) and occurs in the sodium iodate retinal degeneration model (Tang et al, 2021). Taken together, iron may induce retinal degeneration via peroxidation of polyunsaturated fatty acids.…”

Cell Ferroptosis: New Mechanism and New Hope for Retinitis Pigmentosa

“…They first observed that sodium iodate increased intracellular labile iron, while decreasing intracellular glutathione and cysteine. Using deferoxamine or ferrostatin-1, two ferroptosis inhibitors, ARPE-19 cell death was prevented from sodium iodate exposure [110,111]. These studies together support the relatively strong association between RP and ferroptosis (Figure 1).…”

“…However, data on other ferroptosis regulators, such as ferrostatin-1 and liproxstatin-1 on RP models, are still lacking. Recently, two new studies found that ferroptosis is involved in sodium iodate-induced ARPE-19 cell death, suggesting that ferroptosis is involved in retinal degeneration, which supports the association with RP [110,111]. They first observed that sodium iodate increased intracellular labile iron, while decreasing intracellular glutathione and cysteine.…”

miR-3587 Targets HMOX1 to Attenuate Ferroptotic Renal Injury Following Ischemia-Reperfusion

“…HMOX1 is an inducible enzyme that catalyzes heme conversion into biliverdin, carbon monoxide, and free ferrous during oxidative stress. From a mechanistic perspective, HMOX1 can also release carbon monoxide and free iron ions, thereby aggravating oxidative stress [21]. The upregulation of HMOX1 is evident in many different human malignancies, wherein it plays an important role in regulating the stability of the tumor microenvironment in a manner that promotes tumor cell proliferation, angiogenesis, and metastasis [21].…”

“…From a mechanistic perspective, HMOX1 can also release carbon monoxide and free iron ions, thereby aggravating oxidative stress [21]. The upregulation of HMOX1 is evident in many different human malignancies, wherein it plays an important role in regulating the stability of the tumor microenvironment in a manner that promotes tumor cell proliferation, angiogenesis, and metastasis [21]. However, HMOX1 can also promote ferroptosis in cancer cells in therapeutic contexts [22].…”