Metabolic Enzyme Shows Potential as IPF Therapy in Early Study

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Blocking the activity of a metabolic enzyme called succinate dehydrogenase (SDH) promoted the death of myofibroblasts — the main drivers of pulmonary fibrosis (PF) — and helped to heal persistent lung scarring (fibrosis) in a rat model, a study reported.

These benefits were associated with a rescue of the metabolic abnormalities found in the rats’ fibroblasts — cells that mature into myofibroblasts upon tissue injury to promote wound healing, but do so excessively in this disease.

Notably, SDH inhibition was achieved with IR-780, a small fluorescent molecule that selectively accumulated in damaged lung tissues, suggesting that suppressing SDH through the use of IR-780 or other agents may be a way of treating PF.

These findings were reported in the study, “Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis,” published in the journal Redox Biology.

Idiopathic pulmonary fibrosis (IPF), a form of PF with no clear cause, is characterized by excessive wound healing that leads to fibrosis and increased stiffness of lung tissue, making it difficult for patients to breathe.

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Fibroblast maturation into myofibroblasts, which produce excessive levels of fibrosis-associated proteins like collagen, fibronectin, and alpha smooth muscle actin (alpha-SMA), is a key contributing event to IPF. As such, suppressing fibroblast maturation or promoting myofibroblast death are viewed as potential approaches in lessening lung fibrosis.

While previous studies highlighted an association between IPF and metabolic dysregulation, whether these metabolic abnormalities “represent a cause or consequence of IPF remains unclear.”

A team of researchers in China discovered that myofibroblast maturation and fibrosis in a rat model of induced PF is promoted by abnormalities in sugar and fat metabolism, and that targeting such abnormalities reverses these damaging effects.

They first found that lung fibroblasts from rats with induced PF had increased glycolysis and reduced fatty acid oxidation (FAO) compared with those from healthy animals. Glycolysis is the initial step in the breakdown of sugar to produce energy, while FAO produces energy by breaking down fatty molecules.

These metabolic abnormalities — resulting in higher sugar consumption and fatty molecule accumulation in the fibrotic lung — were found to promote myofibroblast maturation.

Further analyses associated this metabolic dysregulation with significantly higher levels of succinate, a molecule involved in several metabolic pathways, in both fibrotic lung tissues and myofibroblasts.

Succinate was found to contribute to greater glycolysis and lesser FAO by stabilizing HIF-1 alpha, a marker of oxygen starvation, which is known to promote myofibroblast maturation.

When analyzing potential mechanisms behind this PF-associated succinate accumulation, researchers found that SDH, a mitochondrial enzyme that typically converts succinate into another molecule called fumarate, was doing the opposite. Of note, mitochondria are the small compartments responsible for producing energy in cells.

These finding suggested that suppressing SDH in the fibrotic lung could lessen fibrosis. The team then looked for molecules that could block SDH’s activity among their library of mitochondria-targeted small fluorescent molecules.

One such molecule, IR-780, was found to selectively accumulate in damaged lung tissue, but not in healthy lungs, and to bind and mildly suppress one of SDH’s subunits, nearly restoring the enzyme’s activity to normal levels.

IR-780 given as a treatment prevented succinate accumulation, excess glycolysis and deficient FAO, and lessened fibrosis and lung dysfunction in the rat model, regardless of whether PF was recently induced or already established.

These beneficial effects were associated with a normalization of the levels of TGF-beta (a known driver of PF), collagen, alpha-SMA, and fibronectin, and with significant reductions in inflammation.

Notably, IR-780 was also found to preferentially enter myofibroblasts relative to fibroblasts, and to promote myofibroblast death by increasing the production of potentially damaging molecules called reactive oxygen species.

Treating rats with IR-780 also doubled their chances of survival, reducing their mortality rate from 80% to 40%.

These findings highlighted that “upregulation of glycolysis and downregulation of FAO contribute to lung fibrosis formation, and this process is caused by a significant accumulation of succinate in fibroblasts,” the researchers wrote.

As such, “succinate dehydrogenase is an exciting new therapeutic target to treat IPF, and IR-780 can be a promising agent to control lung fibrosis by targeting succinate dehydrogenase,” they added.

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