Bisphenol F promotes lung cancer progression by MARK2-driven stimulation of proliferation, suppression of ferroptosis, and activation of EMT

With the increasing application of Bisphenol F (BPF), its close association with cancer progression warrants significant attention. However, the specific role and molecular mechanisms of BPF in non-small cell lung cancer (NSCLC) remain unclear. Therefore, elucidating the mechanisms of BPF action in NSCLC is crucial for scientifically evaluating its safety risks and developing novel strategies for lung cancer prevention and treatment. Our investigations revealed that BPF exposure exhibited a significant dose-response relationship: as the treatment concentration increased, the proliferative capacity of A549 and H1299 cells was progressively enhanced, accompanied by a correlated increase in colony formation ability. Concurrently, ferroptosis inhibition was significantly enhanced in a dose-dependent manner. BPF exposure resulted in a significant decrease in MDA levels in cell lysates, intracellular Fe²⁺ concentration, and GSSG levels, while demonstrating a marked increase in GSH levels. Notably, BPF-induced EMT also intensified in a concentration-dependent manner. Cell migration velocity accelerated with increasing BPF exposure, coinciding with dynamic alterations in canonical EMT markers. In a subcutaneous tumor implantation model, BPF exposure further significantly promoted the growth of lung cancer. Moreover, MARK2, acting as a key effector target of BPF, displayed significantly elevated expression levels that correlated positively with increasing BPF concentrations. Molecular docking further confirmed a strong binding affinity between BPF and MARK2. Clinical correlation analysis further demonstrated that patients exhibiting high MARK2 expression experienced a shortened overall survival compared to controls. Crucially, knockdown of MARK2 expression effectively reversed the BPF-mediated oncogenic phenotypes: it not only markedly attenuated the BPF-induced acceleration of cell proliferation and ferroptosis suppression but also potently blocked the EMT process. These findings demonstrate that BPF-induced MARK2 upregulation activates EMT signaling, promoting malignant phenotypes, including proliferation, migration, and ferroptosis suppression, in lung cancer cells. The dual role of MARK2 as a prognostic indicator and actionable target in BPF-driven carcinogenesis offers new perspectives on environmentally triggered lung cancer pathogenesis and precision therapeutic approaches.