Ten-eleven translocation 3 activates the TGF-like ligand Scube3 to promote renal fibrosis: mechanism and translational potential.

Resident renal fibroblasts are a predominant source for myofibroblasts that produce ECM to contribute to renal fibrosis in the course of chronic kidney disease. The mechanism whereby fibroblast-myofibroblast transition (FMyT) is driven remains incompletely understood. In the present study we investigated the involvement of ten-eleven translocation 3 (TET3) in regulating fibroblast-myofibroblast transit ten-eleven translocation ion and renal fibrosis focusing on the regulatory mechanism and translational potential. We report that TET3 deletion in primary renal fibroblasts dampened myofibroblast transition in response to pro-fibrogenic stimuli. Consistently, conditional deletion of TET3 in quiescent fibroblasts (driven by the Col1a2-Cre) or in myofibroblasts (driven by the Postn-Cre) equally attenuated renal fibrosis in mice. Integrated transcriptomic analysis combining RNA-seq and CUT&Tag-seq uncovered signal peptide CUB-EGF-like domain-containing protein 3 (Scube3) as a novel downstream target for TET3. Co-culture assay confirmed that Scube3 mediated intercellular crosstalk and promoted fibroblast activation in an autocrine/paracrine manner. Importantly, myofibroblast-specific Scube3 depletion significantly ameliorated renal fibrosis in mice. Finally, a small-molecule TET3 degrader Bobcat339 suppressed fibroblast-myofibroblast transition in vitro and mitigated renal fibrosis in vivo. Our data support a role for TET3 in renal fibrosis and provide proof-of-concept that targeting the TET3-Scube3 axis may yield novel therapeutic solutions for treating chronic kidney disease.