Tubular La Ribonucleoprotein 7 Suppresses TGF-β/SMAD3 Signaling and Attenuates Kidney Fibrogenesis

BACKGROUND: TGF-β1/SMAD3 signaling drives organ fibrosis, underscoring the need to identify its endogenous regulators for precision therapies. LARP7, a core component of the 7SK snRNP complex that sequesters cyclin-dependent kinase (CDK)9, has an unexplored role in kidney fibrosis and a potential interplay with TGF-β/SMAD3 signaling. METHODS: Single-cell and spatial transcriptomic analyses combined with immunostaining of human kidney biopsies were used to investigate the association between LARP7 and TGF-β/SMAD3 signaling in CKD patients. In vivo and in vitro models evaluated the expression profile of LARP7 after insults, and its contribution to TGF-β/SMAD3 signaling and fibrosis post-injury. RESULTS: We demonstrated that LARP7, abundantly expressed in normal tubules, was downregulated in CKD patients and inversely correlated with TGF-β/SMAD3 activation. This expression pattern was conserved across ischemic, toxic, and obstructive fibrosis models and recapitulated in TGF-β1-treated tubular epithelial cells, indicating a general link between LARP7 downregulation and enhanced TGF-β/SMAD3 signaling. Further loss-of-function and gain-of-function in vitro studies confirmed that LARP7 acted as a specific disruptor of SMAD3 linker region (T179) phosphorylation-an event that coincided with C-terminal phosphorylation and amplified SMAD3 transcriptional activity. LARP7 mediated this by sequestering CDK9 within the 7SK snRNP, thereby preventing CDK9-SMAD3 interaction and consequently inhibiting SMAD3 T179 phosphorylation and profibrotic transcription. TGF-β1 itself suppressed LARP7 expression, completing a self-reinforcing feedback loop that perpetuates TGF-β/SMAD3 signaling in injured tubular epithelial cells. Further in vivo studies showed that tubule-specific Larp7 deletion exacerbated kidney fibrosis after ischemic injury, whereas its overexpression, either preventatively (pre-fibrosis in an obstructive model) or therapeutically (post-fibrosis in ischemic and toxic models), attenuated functional decline and halted fibrotic progression. CONCLUSIONS: Our findings revealed tubular LARP7 as a key negative regulator of TGF-β/SMAD3-driven kidney fibrogenesis. Targeted overexpression of LARP7 in injured tubular epithelial cells attenuated TGF-β1/SMAD3 signaling and conferred protection against post-injury fibrosis.