Pos0021 Metabolic Targeting by Sodium Pyruvate Prevent Fibroblast-to-Myofibroblast Transition and Fibrotic Remodeling

Background: Systemic sclerosis (SSc), an autoimmune disease with features including fibroblast transition and over-synthesis of extracellular matrix, yet has limited treatment options. Recent studies demonstrate that aberrant fibroblast activation is, at least in part, a consequence of mitochondrial dysfunction and associated metabolic reshaping. Sodium pyruvate, widely used as a nutritional supplement, is the stable form of pyruvate acid which acts as a central hub in several key metabolic pathways including glycolysis, the tricarboxylic acid (TCA) cycle and fatty acid metabolism. Objectives: In the current study, we tested the hypothesis that pyruvate supplementation may improve mitochondrial fitness to ameliorate the metabolic alterations in SSc, and that metabolic rebalancing may exert an anti-fibrotic therapeutic effect in a preclinical model of SSc. Methods: The effect of sodium pyruvate on metabolism, mitochondrial fitness, collagen production and fibroblast-to-myofibroblast transition was evaluated in cultured human dermal fibroblasts derived from SSc patients and healthy donors, in mice with bleomycin-induced experimental skin fibrosis and in precision-cut human skin slices. Outcomes included metabolic flux assays, real-time PCR, IF and IHC staining, cellomics, histomorphometry, hyodroxyproline assays, RNA-seq analysis and data mining of published SSc skin transcriptomic data. Results: Several key regulatory components of pyruvate metabolism such as MPC1, PC and PDK2 were observed to be dysregulated in the skin of SSc patients compared to matched healthy donors in the PRESS cohort. Treatment of SSc fibroblasts with sodium pyruvate improved oxidative phosphorylation (OXPHOS) and mitochondrial potential. Notably, this metabolic correction upon pyruvate supplementation were associated with decreased expression of fibrosis-related genes, including COL1A1 and ACTA2, and decreased synthesis of extracellular matrix. In mice with bleomycin-induced dermal fibrosis, pyruvate supplementation demonstrated pronounced antifibrotic effects at well-tolerated doses, with reduced dermal thickening, hydroxyproline content and myofibroblast numbers. Of note, pyruvate treatment also reduced the upregulation of profibrotic genes, including COL1A1 and ACTA2, in response to TGFbeta in precision-cut slices of healthy human skin. Most notably, RNA sequencing of pyruvate-treated precision cut SSc patient skin sections demonstrated a partial reversal of the SSc-specific gene signature by pyruvate treatment. Conclusion: Sodium pyruvate ameliorates the metabolic alterations and improves mitochondrial fitness to inhibit fibroblast-to-myofibroblast transition and collagen in human dermal fibroblasts, in experimental mouse models of fibrosis and directly in human skin. Our study provides evidence that metabolically targeted therapy offer potential for antifibrotic therapies in SSc. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Xiang Zhou: None declared, Thuong Trinh-Minh: None declared, Cuong Tran-Manh: None declared, Andrea-Hermina Györfi is paid as a speaker by Boehringer Ingelheim and Abbvie, Alexandru-Emil Matei: None declared, Honglin Zhu: None declared, Xuezhi Hong: None declared, Tim Filla: None declared, Jiucun Wang: None declared, Jörg Distler JHWD is stock owner of 4D Science and Scientific Lead of FibroCure., JHWD has consultancy relationships with AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roche and UCB., JHWD has received research funding from AbbVie, Anamar, Argenx, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, ExoTherapeutics, Galapagos, GSK, Inventiva, Kiniksa, Lassen, Novartis, Sanofi-Aventis, RedX, UCB.