POS0327 INACTIVATION OF ALDEHYDE DEHYDROGENASE 3A2 INHIBITS FIBROBLAST ACTIVATION AND TISSUE FIBROSIS

Background: The aldehyde dehydrogenase (ALDH) superfamily composes a group of 20 enzymes that catalyze oxidation. Within this enzyme family, ALDH3A2 stands out for its central role in the oxidation long-chain aldehydes. Of particular interest, substrates include also profibrotic lipid mediators such as sphingosine 1-phosphate or leukotrienes, which have been reported to be deregulated context SSc. Objectives: We aimed investigate fibrotic tissue remodeling Methods: Fibroblast-to-myofibroblast transition was analyzed by quantification ACTA2 /αSMA, assessment stress fiber formation and mRNA protein levels type I collagens. ALDH3A2/Aldh3a2 siRNAs were employed specifically knockdown dermal fibroblasts both vitro vivo . Overexpression achieved -pcDNA transfection. investigated three different mouse models: Bleomycin- cGvHD-induced fibrosis well induced overexpression constitutively active TGFβ receptor (TBRI CA ). Target genes identified RNA sequencing. Results: expression modestly reduced SSc skin compared matched healthy controls. This reduction phenocopied activation signaling, whereas selective inhibition signaling prevented downregulation experimental fibrosis. promoted fibroblast-to-myofibroblast with increased αSMA, enhanced fibers collagen release. In contrast, inhibited fibroblast Moreover, mice ameliorated thickening, myofibroblast differentiation deposition murine models fibrosis: Bleomycin-induced sclerodermatous GvHD-as inflammatory stages TBRI -induced an inflammation-independent model sequencing ALDH3A2-knockdown demonstrated regulates activity network developmental pathways including TGFβ, Wnt, Notch, Hedgehog signaling. Conclusion: demonstrate control is downregulated result endogenous, TGFβ-driven feedback loop. Although modest not sufficient counterbalance aberrant SSc, augmentation endogenous regulation demonstrates potent antifibrotic potential fibrosis, thereby providing first evidence target therapies. Disclosure Interests: Xiaohan Xu: None declared, Yi-Nan Li: Chih-Wei Chen: Thuong Trinh-Minh: Georg Schett: Jörg H.W. Distler Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi UCB, Grant/research support from: Array Biopharma, aTyr, BMS, Novartis, Sanofi-Aventis, RedX, UCB