# KIF18A inactivates hepatic stellate cells and alleviates liver fibrosis through the TTC3/Akt/mTOR pathway

## TL;DR

This study shows that KIF18A reduces liver fibrosis by inhibiting HSC activation through the TTC3/Akt/mTOR pathway.

## Contribution

The study identifies KIF18A as a novel regulator of liver fibrosis via its interaction with TTC3 and the Akt/mTOR pathway.

## Key findings

- KIF18A knockdown promotes liver fibrosis, while overexpression alleviates it in a CCl4-induced mouse model.
- KIF18A suppresses the Akt/mTOR pathway by enhancing TTC3-mediated ubiquitination and degradation of p-AKT.
- KIF18A expression is negatively correlated with HSC activation in fibrotic liver tissues.

## Abstract

Activation of hepatic stellate cells (HSCs) has been demonstrated to play a pivotal role in the process of liver fibrogenesis. In this study, we observed a decrease in the expression of KIF18A in fibrotic liver tissues compared to healthy liver tissues, which exhibited a negative correlation with the activation of HSCs. To elucidate the molecular mechanisms underlying the involvement of KIF18A, we performed in vitro proliferation experiments and established a CCl4-induced liver fibrosis model. Our results revealed that KIF18A knockdown enhanced HSCs proliferation and reduced HSCs apoptosis in vitro. Mouse liver fibrosis grade was evaluated with Masson’s trichrome and alpha-smooth muscle actin (α-SMA) staining. In addition, the expression of fibrosis markers Col1A1, Stat1, and Timp1 were detected. Animal experiments demonstrated that knockdown of KIF18A could promote liver fibrosis, whereas overexpression of KIF18A alleviated liver fibrosis in a CCl4-induced mouse model. Mechanistically, we found that KIF18A suppressed the AKT/mTOR pathway and exhibited direct binding to TTC3. Moreover, TTC3 was found to interact with p-AKT and could promote its ubiquitination and degradation. Our findings provide compelling evidence that KIF18A enhances the protein binding between TTC3 and p-AKT, promoting TTC3-mediated ubiquitination and degradation of p-AKT. These results refine the current understanding of the mechanisms underlying the pathogenesis of liver fibrosis and may offer new targets for treating this patient population.

The online version contains supplementary material available at 10.1007/s00018-024-05114-5.