AKF-PD alleviated liver fibrosis by inducing hepatic stellate cell ferroptosis via the HIF-1α/SLC7A11 pathway

Liver fibrosis occurred with persistent activation of hepatic stellate cells (HSCs), which disrupts the balance between deposition and dissolution of extracellular matrix in the liver. One strategy to solve the problem is promoting the inactivation or apoptosis of HSCs. Fluorofenidone (AKF-PD), which was developed by Central South University, is a pyridone with a broad-spectrum anti-organ fibrosis effect. The compound was approved to enter the National Class 1.1 New Drug Phase Ⅱ clinical trial (Lot Number: 2016L09979) in 2016. Our previous study found that AKF-PD has significant anti-liver fibrosis effects in animal liver fibrosis models. However, the exact mechanism by which AKF-PD worked is still under investigation. In this study, we proved that AKF-PD played an anti-liver fibrosis effect by inducing ferroptosis of HSCs. Ferroptosis is a type of programmed cell death that mainly manifests in iron-dependent lipid peroxide accumulation and rupture of the membrane system. Several signaling pathways were involved in the initiation of ferroptosis. Here, we present evidence demonstrating that AKF-PD induced ferroptosis in HSCs and alleviated liver fibrosis through inhibiting the HIF-1α/SLC7A11 signaling pathway.