Mechanism of ECM Stiffness-Integrin-Hippo-ABCG1 axis in regulating ferroptosis and targeted nanodrug intervention in LUAD.

BACKGROUND: Recent advances in mechanobiology have established extracellular matrix (ECM) stiffness as a critical biomechanical cue promoting lung adenocarcinoma (LUAD) metastasis and therapy resistance through mechano-transduction pathways. Ferroptosis is vital in health and disease, regulating LUAD cell death through iron and lipid peroxidation. How mechanical signals are transduced into the electrochemical determinants that govern ferroptosis remains fundamentally unexplored. METHODS: LUAD cells were cultured on polyacrylamide (PA) hydrogel of varying stiffness to mimic physiological and pathological ECM conditions. Transcriptome sequencing (RNA-seq) was employed to identify differential expressed genes (DEGs) across varying ECM stiffness conditions, followed by molecular validation of potential regulatory mechanisms through in vitro experiments, in vivo studies, and clinical samples. Based on this mechanistic insight, we aimed to develop nanocarriers for drug encapsulation and assess their therapeutic efficacy in vitro. RESULTS: Our study have demonstrated that elevated ECM stiffness suppressed ferroptosis in LUAD cells. Mechanistically, high ECM stiffness elevated integrin levels, suppressed the Hippo pathway, and increased YAP levels, which upregulated the downstream molecule ATP-Binding Cassette G1 (ABCG1), thereby reducing ferroptosis sensitivity. This mechanistic model was rigorously validated through a combination of stepwise molecular knockdown experiments in vitro, supporting animal studies in vivo, and analyses of clinical patient samples. Notably, dihydromyricetin (DMY) downregulated ABCG1 expression and sensitized cells to ferroptosis, which was further enhanced by nanocarrier-mediated drug delivery for improved therapeutic outcome. CONCLUSION: Our findings revealed a novel mechanism by which ECM stiffness regulated ferroptosis via the Integrin-Hippo-ABCG1 pathway in LUAD. Nanodrugs designed to target ABCG1 demonstrate significant potential for future LUAD therapy by resensitizing tumors to ferroptosis (Fig. 1).