RNA binding motif single-stranded interacting protein 1 drives renal fibrosis by stabilizing Annexin A8 mRNA to activate PI3K/AKT signaling.

Renal fibrosis represents a significant pathological hallmark of chronic kidney disease (CKD), yet therapeutic strategies for its management remain notably inadequate. RNA-binding motif single-stranded interacting protein 1 (RBMS1), an RNA-binding protein (RBP) previously implicated in cancer progression and fibrosis, remains poorly understood within the context of renal fibrosis. The current investigation demonstrates elevated RBMS1 expression in kidney tissues from CKD patients, fibrotic mouse models, and transforming growth factor-β1 (TGF-β1)-induced rat renal fibroblasts. Fibroblast-specific conditional knockout of RBMS1 in mice markedly ameliorated renal injury and fibrosis, accompanied by reduced fibrotic marker expression. Similarly, siRNA-mediated knockdown of RBMS1 in renal fibroblasts suppressed TGF-β1-induced fibroblast activation, proliferation, and migration. RNA-seq and RIP assays revealed Annexin A8 (ANXA8) as a key downstream target of RBMS1. RBMS1 directly bound the coding region of ANXA8 mRNA via its RRM2 domain, thereby enhancing transcript stability. ANXA8 overexpression activated fibroblasts and promoted PI3K/AKT signaling, whereas ANXA8 knockdown abolished the pro-fibrotic effects of RBMS1. Pharmacological inhibition of RBMS1 with nortriptyline (NTP) significantly attenuated renal fibrosis in unilateral ureteral obstruction (UUO) mice. These results reveal an RBMS1/ANXA8/PI3K/AKT regulatory axis in renal fibrosis, highlighting RBMS1 as a potential therapeutic target.