Almonertinib inhibits liver cancer progression by triggering autophagy-dependent ferroptosis through inhibition of the PI3K/Akt1/mTOR pathway

Abstract

Liver cancer ranks among the most prevalent and lethal malignancies globally, with most patients presenting at an advanced stage at initial diagnosis. Although multiple treatment modalities exist-including surgical resection, interventional therapy, targeted therapy, and immunotherapy-outcomes for patients with advanced liver cancer often remain suboptimal. To broaden the scope of cancer treatment, drug repurposing has emerged as a promising strategy. In this study, we systematically evaluated the potential of the third-generation EGFR-TKI Almonertinib to inhibit liver cancer progression in vivo and in vitro. First, functional assays confirmed that Almonertinib effectively suppressed the proliferation, migration, and invasive capabilities of HepG2 and MHCC-97H cells. Subsequently, by investigating the precise type of cell death induced by Almonertinib, we discovered that it activates autophagy-dependent cell death in HepG2 and MHCC-97H cells via the PI3K/Akt1/mTOR pathway. Additionally, Almonertinib induces ferroptosis in liver cancer cells by suppressing the expression of the antioxidant pathway SLC7A11/GSH/GPX4. Interestingly, we demonstrated that Almonertinib-activated autophagy directly participates in ferroptosis activation by promoting Fe²⁺ release upstream and influencing lipid peroxidation, elucidating the occurrence of autophagy-dependent ferroptosis. In summary, these findings indicate that Almonertinib suppresses liver cancer progression by inducing autophagy-dependent ferroptosis in HepG2 and MHCC-97H cells, potentially providing insights for positioning Almonertinib as a novel therapeutic candidate for future liver cancer treatment.

Keywords: Almonertinib; Autophagy; Ferroptosis; Lipid peroxidation; Liver cancer.