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Systemic sclerosis

SIX1 and PAI-1 emerge as therapeutic targets in systemic sclerosis

Nature Reviews Rheumatology volume 22, page 218 (2026)Cite this article

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The findings of two studies published in JCI Insight suggest that the transcription factor SIX1 and its downstream mediator plasminogen activator inhibitor 1 (PAI-1) could be promising therapeutic targets for systemic sclerosis (SSc) and demonstrate the efficacy of the small-molecule PAI-1 inhibitor MDI-2517 in a preclinical model of the disease.

In one study, Wareing et al. sought to explore the mechanisms linking dermal white adipose tissue (DWAT) loss with fibrosis in SSc and the contribution of SIX1, which had previously been implicated as a driver of fibrosis, in this process. They showed that expression of SIX1 was increased in SSc-affected human skin samples, and that increased levels of SIX1 in adipocytes correlated with loss of DWAT in SSc skin.

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  1. Nature Reviews Rheumatology http://www.nature.com/nrrheum/

    Sarah Onuora

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  1. Sarah Onuora
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Correspondence to Sarah Onuora.

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Onuora, S. SIX1 and PAI-1 emerge as therapeutic targets in systemic sclerosis. Nat Rev Rheumatol 22, 218 (2026). https://doi.org/10.1038/s41584-026-01367-5

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