Type of cell death called ferroptosis may be SSc therapeutic target

Computer analysis was used to compare genes from healthy people, patients

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A type of cell death called ferroptosis and the genes related to it may play a role in systemic sclerosis (SSc), meaning they could be used as potential targets to treat the disease, a bioinformatics study suggests.

The study, “Comprehensive analysis of ferroptosis-related hub gene signatures as a potential pathogenesis and therapeutic target for systemic sclerosis: A bioinformatics analysis,” was published in the International Journal of Immunopathology and Pharmacology.

Overly active immune cells in SSc, or scleroderma, lead to hardened, thickened patches of skin and sometimes problems with internal organs. What causes this to happen is unclear.

Ferroptosis depends on iron inside cells, causing damage to phospholipids, fats that make up a cell’s membrane. This damage can cause cell death, which is thought to play a role in many different types of diseases and injuries to organs.

To find out if ferroptosis plays a role in scleroderma, researchers in China used a type of computer analysis called bioinformatics to compare sets of genetic data from people with SSc and healthy people.

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Comparing genetic data in SSc patients, healthy people

The goal was to identify differentially expressed genes, those more active (upregulated) or less active (downregulated) in scleroderma. This helps to understand what genes are involved in specific diseases.

“There is a pressing need for a deeper comprehension of SSc as well as for the development of new biomarkers and treatment targets,” the researchers wrote.

The datasets (GSE125362 and GSE76807) were from the Gene Expression Omnibus public repository and included genetic data from tissue samples of 18 people with SSc and nine healthy (control) people.

A total of 24 ferroptosis-related genes were differentially expressed in people with SSc versus controls, suggesting they may be involved in both ferroptosis and SSc. Fourteen were upregulated and 10 were downregulated.

GO annotation analysis, a way to figure out what genes do, revealed they had functions in slowing or stopping cell growth, in inflammation, and in producing proteins.

KEGG pathway analysis, which helps understand the interactions of genes by mapping them on to known biological pathways, revealed that the genes were involved in necroptosis (a type of inflammatory cell death), the NOD-like receptor signaling pathway (which detects and responds to harmful germs), fats, and atherosclerosis.

The hub (core) genes — those with many connections within biological pathways and play a central role in controlling how cells function — were CYBB, IL6, NOX4, TLR4, CXCL2, JUN, and LY96.

Immune cells in skin samples

The researchers also looked at immune cells in skin samples from five people with SSc and five healthy people, ages 18-80.

Compared with the controls, the skin of people with SSc had more active natural killer (NK) cells. NK cells detect and eliminate infected and diseased cells. But there were fewer resting dendritic, NK, and mast cells. Dendritic cells capture foreign or harmful substances and present them to other immune cells to activate an immune response. Mast cells play a key role inflammation and are activated to release a number of inflammatory mediators.

In the skin samples, the levels of IL-6 protein were significantly higher in SSc than controls. IL-6 is an inflammatory molecule with a known role in SSc and the target of Actemra (tocilizumab). Levels of CYBB, part of a group of proteins that plays a key role in the immune system, were significantly lower in SSc than healthy people.

The findings suggest ferroptosis may play a role in SSc. Key genes such as IL-6 and CYBB were identified as being related to ferroptosis in the disease. “Ferroptosis and related genes might be promising targets in the treatment of SSc,” the researchers wrote.

A search for known molecules that could target any of the 24 differentially expressed genes revealed a list of 10 “potential treatment options.” They were nafcillin, minoxidil, ketorolac, daunorubicin, apafant, toremifene, ranolazine, warfarin, cortisone-acetate, and dinaciclib.