Postbiotics Combination Synergises the Anti-Proliferative Effects of Doxorubicin in Gastric Cancer Cells: A Cellular and Molecular Deep Dive

Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are microbial me-tabolites with recognised roles in gut and immune homeostasis, but their therapeutic relevance in gastric cancer, particularly in combination with chemotherapeutics, re-mains unclear. This study investigated the antiproliferative synergy between a com-bined SCFA mixture (APB) and doxorubicin (Dox) in AGS gastric adenocarcinoma cells using integrated cellular, molecular, and proteomic approaches. APB and Dox each inhibited cell proliferation, with IC₅₀ values of 568.33 ± 82.56 μg/mL and 0.22 ± 0.04 μg/mL, respectively, and their combination (3000 + 0.27 μg/mL) enhanced cyto-toxicity, achieving 103.46% inhibition and reducing the APB IC₅₀ to 512.80 ± 18.37 μg/mL. Combination Index values confirmed synergistic interactions (CI₅₀ = 0.61; CI₉₅ = 0.13). APB+Dox significantly increased apoptosis (94.83%) with minimal necrosis (4.64%) and induced strong ROS generation comparable to APB alone, while Dox showed limited oxidative effects. Proteomic profiling revealed downregulation of ri-bosomal proteins and cell cycle regulators in Dox and APB+Dox groups, with the com-bination further enhancing apoptosis-related pathways and stress responses. Overall, these findings indicate that SCFA-based interventions, exemplified by APB+Dox, may offer a low-toxicity strategy to potentiate chemotherapy efficacy in gastric cancer through apoptosis induction, redox disruption, and attenuation of drug resistance.