SNX3 exacerbates hepatic fibrosis by amplifying TGF-β1/Smad signaling pathway in hepatocyte-HSC fibrotic loop

Abstract

Hepatic fibrosis is a chronic disease driven by dysregulated TGF-β1-mediated interactions between hepatocytes and hepatic stellate cells. The molecular mechanisms controlling TGF-β1 degradation versus secretion remain poorly understood. Here, we identify sorting nexin 3 (SNX3), a retromer-associated cargo-binding protein, as a critical regulator of TGF-β1-driven hepatic fibrosis. SNX3 expression was significantly elevated in liver tissues from fibrosis patients and mouse models, correlating positively with TGF-β1 signaling. Functional studies using conditional mouse models demonstrated that hepatocyte-specific SNX3 knockout provided substantial protection against fibrosis, while overexpression induced spontaneous liver fibrosis. Mechanistically, SNX3 binds TGF-β1 and prevents its lysosomal degradation by promoting retention in early endosomes, thereby enhancing secretion. In hepatocytes, SNX3 increases TGF-β1 secretion that activates neighboring hepatic stellate cells through paracrine signaling. In activated hepatic stellate cells, elevated SNX3 expression further amplifies TGF-β1 production, creating a self-perpetuating fibrotic cascade leading to enhanced downstream signaling and transcriptional activation of fibrotic genes. Pharmacological studies validated therapeutic potential, with TGF-β1 signaling inhibition attenuating SNX3-induced fibrosis while pathway activation abolished SNX3 knockout protection, establishing SNX3 as a promising therapeutic target.