Crosstalk of metabolic and epigenetic pathways in systemic sclerosis (SSc)

The project aimed to investigate metabolic dysregulations and its effect on development of skin fibrosis in systemic sclerosis (SSc). We have identified dimethyl-alpha ketoglutarate (dm-akg) as a potential suppressor of myofibroblast activation in SSc. Our extensive in vitro analyses showed that dm-akg can efficiently inhibit profibrotic and proinflammatory responses of skin fibroblasts by interfering with the TGFβ-induced myofibroblast differentiation (alpha-smooth muscle protein, cytoskeleton organization, secretion of the extracellular matrix proteins) and function (contraction, migration, invasion, proliferation). Further scRNAseq analysis of ex-vivo treated SSc skin tissues explants identified fibroblasts as the main cell target of dm-akg within skin tissue with predominant transcriptomic effect on suppression of fibrotic and inflammatory pathways. Thus, our results strongly suggest that dm-akg might be a novel repressor of pathogenic myofibroblast reprogramming and skin fibrosis in SSc.

Metabolic dysregulation lies at the core of fibrotic diseases, such as systemic sclerosis, and its modulation might be directly involved in development of fibrosis. In our project we have identified an important cell metabolite analogue, dimethyl alpha-ketoglutarate (dm-akg) as a potential novel suppressor of extracellular matrix deposition in systemic sclerosis. Our in vitro and ex vivo analysis revealed its strong effect on suppression of profibrotic and inflammatory responses in human dermal fibroblasts and in fibrotic skin tissue. Thus, dm-akg represent a potential novel anti-fibrotic compound for treatment of skin fibrosis and additional testing is needed to determine its in vivo efficacy and exact mechanism of action, leading to development of more specific and stable analogs.

• ACR 2019 Poster: The Metabolic Intermediate Alpha-Ketoglutarate Suppresses the TGF beta-driven Profibrotic Responses of Dermal Fibroblasts

• 16th International Workshop on Scleroderma Research 2019, Poster and Oral presentation: Metabolic intermediate alpha-ketoglutarate attenuates TGFB-driven responses of dermal fibroblasts

• ACR 2021 Poster: Metabolic Intermediate Dimethyl-Alpha-Ketoglutarate Is a Novel Repressor of Pathogenic Myofibroblast Reprogramming and Skin Fibrosis in Systemic Sclerosis

EULAR Abstracts

2020

• SAT0292: Integrative transcriptomic and functional analysis reveals a role of dimethyl-α-ketoglutarate in TGFβ-driven cytoskeleton regulation and myofibroblast differentiation
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