Background/Purpose: Systemic sclerosis (SSc) is a progressive fibrotic disease characterized by fibroblast activation and immune dysregulation, with limited therapeutic options. Mitochondrial dysfunction is increasingly implicated in fibrosis, yet the role of mitochondrial translation remains underexplored. Linezolid, a clinically approved ribosome-targeting antibiotic, inhibits mitochondrial protein synthesis. We investigated whether targeting mitochondrial translation with linezolid could mitigate fibrosis in SSc.

Methods: We employed complementary SSc models, including TGFβ-stimulated human dermal fibroblasts, three-dimensional SSc skin equivalents (SScSE), and precision-cut skin slices (PCSS) from SSc patients. In vivo, we used a multiorgan fibrosis mouse model mimicking key features of diffuse cutaneous SSc. Mechanistic studies included immunostaining, Western blot, Seahorse analysis, and nascent mitochondrial translation assays. Transcriptomic profiling was performed on fibroblasts, SSc tissue, and TGFβ-activated macrophages.

Results: Linezolid inhibited TGFβ-induced fibroblast activation across multiple models of SSc, including cultured human dermal fibroblasts, three-dimensional SSc skin equivalents (SScSE), SSc patient-derived precision-cut skin slices (PCSS), and an inflammation-driven murine fibrosis model. Treatment reduced αSMA expression, stress fiber formation, and collagen type I deposition, indicating effective suppression of fibroblast-to-myofibroblast transition.Transcriptomic analyses revealed that linezolid reversed profibrotic gene expression programs and downregulated key signaling pathways such as TGFβ, WNT, and JAK-STAT. In SScSE, linezolid also modulated macrophage activation profiles, suppressing pathways involved in cytoskeletal remodeling and fibroblast stimulation.Mechanistically, linezolid impaired mitochondrial translation in fibroblasts, evidenced by reduced incorporation of nascent mitochondrial proteins and decreased MTCO1 expression. This was accompanied by diminished oxidative phosphorylation capacity and lowered NAD⁺/NADH ratios, contributing to functional metabolic disruption.

Conclusion: This study identifies mitochondrial translation as a critical regulator of fibroblast activation and immune cell function in SSc. By targeting this pathway, linezolid exerts potent antifibrotic effects across human and murine models. Given its clinical availability, these findings provide strong rationale for repurposing linezolid as a novel therapeutic strategy for fibrotic disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/linezolid-prevents-fibroblast-activation-and-ameliorates-tissue-fibrosis-by-inhibition-of-mitochondrial-translation/