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

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.

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