Promoting cell death process may help to limit skin fibrosis in SSc

Ferroptosis, a cell death process that can help to regulate uncontrolled cell growth, was suppressed in skin cells from people with systemic sclerosis (SSc), according to recent research.

Such suppression appears to be mediated by increased activity of an antioxidant protein called GPX4.

Researchers believe that targeting GPX4 to increase ferroptosis could offer a way of preventing the uncontrolled cell growth that drives scar tissue buildup, or fibrosis, in the skin of SSc patients.

The study, “Upregulation of GPX4 drives ferroptosis resistance in scleroderma skin fibroblasts,” was published in Free Radical Biology and Medicine.

Skin fibrosis in SSc tied to excess of fibroblasts and collagen

SSc, also known as scleroderma, is an autoimmune disease wherein scar tissue accumulates in the skin and, in another disease type, in internal organs as well. Skin fibrosis is caused by the rapid and uncontrolled growth, or proliferation, of cells called fibroblasts and excessive production of collagen, a connective tissue protein.

However, it is not clear what initially drives these processes, and current disease treatments aim to manage symptoms associated with scleroderma. No available therapies are specifically designed to target fibrosis in SSc, the study’s researchers stated.

Programmed cell death refers to types of cell death that occur naturally and serve important biological functions. Ferroptosis is one form of programmed cell death that’s believed to help prevent the excessive cell growth that characterizes cancer.

In ferroptosis, iron triggers the overproduction of toxic reactive oxygen species (ROS) molecules. This leads to a state of oxidative stress, an imbalance between ROS and the antioxidant molecules that counterbalance them, which ultimately drives cell death. As such, antioxidants can regulate ferroptosis.

This form of programmed cell death has been identified as a possible therapeutic target in SSc, but the exact relationship remains to be thoroughly investigated.

GPX4, antioxidant that blocks ferroptosis, found at high levels in patient cells

Researchers at Fudan University in China further explored the possible role of ferroptosis in SSc by examining skin fibroblasts taken from scleroderma patients. The cells were collected and treated in the lab with erastin, a substance that induces ferroptosis.

Fewer signs of erastin-mediated cell death were evident in patients’ cells than those of healthy people, reflecting a resistance to ferroptosis in SSc.

Correspondingly, molecules associated with iron transport were dysregulated in the SSc cells. After erastin exposure, the activity (expression) of a molecule known as TfR1 was lower whereas that of one called DMT1 was higher.

Iron levels increased upon erastin exposure in both SSc and healthy cells, but no differences were observed between the two groups.

ROS production was inhibited in erastin-exposed SSc cells, whereas ferritin production, which is involved in iron storage and helps to prevent ferroptosis, was increased.

GPX4, an antioxidant enzyme critical for ferroptosis inhibition, was elevated in SSc cells compared to healthy ones before erastin treatment. While erastin helped in its suppression, GPX4 levels remained higher in SSc cells.

When GPX4 was inhibited in SSc cells with a ferroptosis-inducing molecule called RSL3, erastin-induced cell death significantly increased, suggesting that “upregulation of GPX4 in SSC fibroblasts was a critical contributor to erastin resistance,” the researchers wrote.

As such, “inhibition of GPX4 in skin fibroblasts could be a promising therapeutic approach for SSC skin fibrosis,” they added.

Further research using blood samples from scleroderma patients and disease animal models, the scientists noted, should be conducted to confirm this study’s findings.