PREX1 regulates renal fibrosis through the RPTOR-mTORC1 signaling pathway

Renal fibrosis is a progressive pathological process driving chronic kidney disease (CKD) toward end-stage renal failure, yet effective anti-fibrotic therapies remain unavailable. The mTORC1 pathway critically promotes fibrosis by enhancing extracellular matrix (ECM) production and myofibroblast activation, but its upstream regulatory mechanisms in the kidney are poorly defined. Here, we identify PREX1 as a novel upstream activator of mTORC1 in renal fibrosis. We show that PREX1 drives fibrogenesis by positively regulating RPTOR, a core component of the mTORC1 complex. In human fibrotic kidneys and murine UUO models, PREX1 was markedly upregulated and closely correlated with ECM deposition. Mechanistically, PREX1 and RPTOR were found to reside in the same protein complex, and PREX1 increased RPTOR abundance; whether this association is direct was not determined. Silencing RPTOR abolished PREX1-driven S6K1 phosphorylation, placing RPTOR downstream of PREX1 in mTORC1 activation. Importantly, genetic silencing of either PREX1 or RPTOR, both in vitro and in vivo, significantly suppressed fibrotic and inflammatory responses and ameliorated renal pathology. Collectively, our findings uncover a novel PREX1-RPTOR-mTORC1 signaling axis that governs renal fibrogenesis and highlight the PREX1-RPTOR-mTORC1 axis as a promising therapeutic target for chronic kidney disease.