Mitochondrial function was evaluated using Seahorse assays alongside mitochondrial protein synthesis assessments.<h4>Results</h4>Linezolid inhibited TGFβ-induced fibroblast activation in cultured human fibroblasts, SScSE, sclGvHD mice, and SSc-PCSS, as demonstrated by reversal of profibrotic gene expression programs, downregulation of TGFβ, WNT, and JAK-STAT signaling, and reductions in αSMA expression or stress fiber formation, which led to reduced collagen deposition and ameliorated skin or lung fibrosis in vivo. This evidence concerns the gene TGFB1 and systemic sclerosis.