Hepatic Stellate Cell TM4SF1 Accelerates Hepatic Fibrosis Progression via Interacting With the Tyrosine Kinase c-Src.

Background & Aims: Identifying genes involved in hepatic stellate cell (HSC) activation is essential for understanding hepatic fibrosis (HF). The role of Transmembrane 4 L six family member 1 (TM4SF1) in HF is not well understood, despite recent investigations into its involvement in various malignant tumors.

Methods: Bioinformatics analysis identified key genes involved in HSC activation. TM4SF1 expression levels in patients, mouse models, and primary mouse HSCs were measured. Silencing or overexpressing TM4SF1 in the human HSC line LX-2 was used to assess the regulatory role of TM4SF1 on HSC activation. HSC-specific TM4SF1 overexpressed and knockout mice were used to study the role of TM4SF1 in HSC activation in vivo.

Results: Single-cell pseudotiming analysis identified TM4SF1 as a key gene in HSC activation. TM4SF1 expression was elevated in patients with fibrosis, mouse models, and activated primary mouse HSCs. Overexpression and knockdown of TM4SF1 in LX-2 cells confirmed its role in promoting HSC proliferation, migration, and activation through the c-Src/PI3K/AKT pathway. Further experiments showed that TM4SF1 binds to and activates the tyrosine kinase c-Src. The Src family inhibitor saracatinib inhibited the up-regulation of the c-Src/PI3K/AKT pathway and the aggravation of fibrosis caused by the overexpression of TM4SF1 in HSCs. Finally, HSC-specific TM4SF1 knockout in mice inhibited HSC activation and alleviated HF by down-regulating the c-Src/PI3K/AKT pathway.

Conclusions: TM4SF1 promotes HF progression and HSC activation by binding to and activating c-Src. TM4SF1 could be a future therapeutic target for HF by inhibiting HSC activation.