The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways

TLDR

Long noncoding RNAs regulate key cellular processes including proliferation, cell death, and differentiation. The study investigates whether the liver‑enriched lncRNA lnc‑LFAR1 promotes liver fibrosis. Lnc‑LFAR1 binds Smad2/3, enhances its interaction with TGFβR1 and phosphorylation, and upregulates transcription of TGFβ, Smad2/3, Notch2/3, thereby activating TGFβ and Notch signaling. Silencing lnc‑LFAR1 suppresses hepatic stellate cell activation, reduces TGFβ‑induced hepatocyte apoptosis, and alleviates CCl4‑ and bile duct ligation‑induced fibrosis in mice, revealing a positive feedback loop between TGFβ/Smad2/3 and Notch pathways and positioning lnc‑LFAR1 as a therapeutic target.

Abstract

Abstract Long noncoding RNAs (lncRNAs) play important roles in various biological processes such as proliferation, cell death and differentiation. Here, we show that a liver-enriched lncRNA, named liver fibrosis-associated lncRNA1 (lnc-LFAR1), promotes liver fibrosis. We demonstrate that lnc-LFAR1 silencing impairs hepatic stellate cells (HSCs) activation, reduces TGFβ-induced hepatocytes apoptosis in vitro and attenuates both CCl 4 - and bile duct ligation-induced liver fibrosis in mice. Lnc-LFAR1 promotes the binding of Smad2/3 to TGFβR1 and its phosphorylation in the cytoplasm. Lnc-LFAR1 binds directly to Smad2/3 and promotes transcription of TGFβ, Smad2, Smad3, Notch2 and Notch3 which, in turn, results in TGFβ and Notch pathway activation. We show that the TGFβ1/Smad2/3/lnc-LFAR1 pathway provides a positive feedback loop to increase Smad2/3 response and a novel link connecting TGFβ with Notch pathway. Our work identifies a liver-enriched lncRNA that regulates liver fibrogenesis and suggests it as a potential target for fibrosis treatment.