Abstract

Oral squamous cell carcinoma (OSCC) presents significant therapeutic challenges due to chemoresistance and limited treatment modalities. Black phosphorus nanosheets (BPNSs), a novel two-dimensional nanomaterial, have shown promising antitumor effects. However, their role in inducing ferroptosis in OSCC and the underlying mechanisms remain to be elucidated. In this study, BPNSs were prepared via liquid-phase exfoliation, and their effects on the OSCC CAL-27 cells were subsequently evaluated. In vitro, BPNSs dose-dependently inhibited CAL-27 cell proliferation, induced G2/M phase arrest, and triggered ferroptosis, indicated by increased intracellular Fe2+, ROS, and lipid peroxidation, along with decreased glutathione (GSH) levels and altered expression of ferroptosis-related proteins (ACSL4, NCOA4, and GPX4). These effects were attenuated by ferroptosis inhibitor ferrostatin-1. In vivo, BPNSs suppressed CAL-27 xenograft growth without systemic toxicity, with elevated tumor malondialdehyde (MDA) and Fe2+ confirming ferroptosis. Mechanistic studies indicated that BPNSs inhibited the PI3K-AKT pathway, leading to the downregulation of SREBP1. Overexpression of SREBP1 attenuated BPNS-induced ferroptosis, confirming its critical role. These findings suggest that BPNSs induce ferroptosis in OSCC via the PI3K-AKT-SREBP1 signaling pathway, providing a novel therapeutic strategy for OSCC treatment.