7-Deshydroxypyrogallin-4-carboxylic acid dietary phytochemical as a putative FTO inhibitor in breast cancer: an integrated computational and cytotoxicity study.

Abstract

Breast cancer is the most frequently diagnosed malignancy in women globally, representing a major global health burden, with a significant subset of cases exhibiting resistance to standard therapeutic regimens. Recently, m6A RNA demethylases such as FTO have been identified as important oncogenes in breast cancer, which modify the epitranscriptome of tumor cells to favor expression of growth-promoting genes while suppressing expression of anti-apoptotic genes. In this study, we performed virtual screening of 1,000 dietary compounds targeting the FTO protein in order to discover potential therapies for breast cancer. 7-Deshydroxypyrogallin-4-carboxylic acid (DCA) was identified as the top-ranked candidate. Molecular dynamics (MD) simulations of DCA-FTO complex displayed the formation of stable hydrogen bonds for 200 ns of MD simulations. The ADMET-prediction of DCA showed high gastrointestinal tract absorption and is not expected to be Ames-toxic. The effect of DCA on the growth of MCF-7 human breast cancer cells was assessed by Sulforhodamine B (SRB) cytotoxicity assays and found to be dose- and time-dependent. The IC₅₀ values for the growth inhibition of MCF-7 breast cancer cells were found to be 90.7 µg/mL (365.4 µM) after 24 h of treatment and 40.8 µg/mL (164.4 µM) after 48 h. As a secondary exploratory analysis, lupinine was computationally evaluated against NQO1; however, its suboptimal binding stability and safety concerns preclude experimental advancement at this stage. These findings provide a preliminary mechanistic and experimental framework for DCA as a dietary FTO inhibitor in breast cancer, necessitating further validation through orthogonal target engagement assays, m6A quantification, and in vivo tumor models.