Targeting paraoxonase-2 overcomes chemoresistance in triple-negative breast cancer cells by inducing extensive metabolic and molecular remodeling

Triple-negative breast cancer (TNBC) remains an aggressive malignancy characterized by limited therapeutic options and a high propensity for chemoresistance. Increasing evidence indicates that metabolic and redox-regulating enzymes are pivotal in driving TNBC progression and survival under pharmacological stress. In this study, we investigated whether paraoxonase-2 (PON2), a key modulator of oxidative stress and mitochondrial function, may represent a potential target to enhance the efficacy of cytotoxic chemotherapy. Using the human triple-negative breast cancer MDA-MB-231 cell line, we combined cell viability assays with Fourier Transform Infrared Microspectroscopy (FTIRM) and multivariate and univariate statistical analyses to evaluate the effects of PON2 silencing on the cellular response to doxorubicin and 5-fluorouracil. This label-free vibrational spectroscopic approach was used to monitor chemotherapy-induced biochemical changes and investigate the molecular remodeling associated with PON2 knockdown. PON2 silencing significantly impaired cell proliferation and enhanced the sensitivity of TNBC cells to both chemotherapeutic agents. FTIRM analysis revealed spectral modifications consistent with treatment-induced alterations in the main cellular macromolecular components. These changes suggest that PON2 silencing affects the ability of TNBC cells to maintain biochemical homeostasis under pharmacological stress. Overall, this study highlights the relevance of PON2 in sustaining the adaptive response of TNBC cells to chemotherapy and supports FTIRM as a powerful analytical approach to identify molecular signatures associated with chemotherapeutic response.