Fuelling the Fight from the Gut: Short-Chain Fatty Acids and Dexamethasone Synergise to Suppress Gastric Cancer

Short-chain fatty acids (SCFAs) are microbial metabolites, also known as postbiotics, produced by the gut microbiota, essential in maintaining gut health. Research on the antiproliferative effects of SCFAs against gastric cancer cells and their interactions with conventional cancer therapies is limited. This study investigates the antiproliferative effects of SCFA salts—magnesium acetate (A), sodium propionate (P), and sodium butyrate (B)—and their combinations with dexamethasone (Dex) in AGS gastric adenocarcinoma cells. Our results showed that SCFA salts were potent against AGS cells, and combining A, P, and B (APB) also led to significant growth inhibition of the cells, with an IC50 of 568.33 μg/mL. Furthermore, combining APB with Dex enhanced the antiproliferative effect of the former, showing strong synergy against AGS cells with a combination index value of 0.76. Flow cytometry analysis confirmed that both APB (p < 0.0001) and APB+Dex (p < 0.0001) induced substantial apoptosis in AGS cells compared to the negative control, with minimal necrosis, suggesting a primarily apoptotic mode of cell death. Additionally, APB (p < 0.0001) alone significantly elevated reactive oxygen species (ROS) levels, with Dex moderating this increase in the APB+Dex group (p < 0.0001), compared to the untreated control. Proteomic analysis using LC-MS identified several protein groups in the AGS cells after treatment with APB, Dex, and their combination APB+Dex. Proteomics revealed that APB suppressed key regulators of the cell cycle checkpoint (e.g., CHEK1, log2FC = –1.31), chromatin remodelling (e.g., CREBBP, –1.14), and DNA repair enzymes (e.g., BRCA1, –1.40), indicating a disruption of proliferation and genome maintenance machinery in AGS gastric adenocarcinoma cells. In contrast, Dex induced transcriptional reprogramming via modulation of CDKN1A (p21, 1.01), alongside activation of cholesterol biosynthesis through HMGCR (3.33), and enhancement of ferroptosis-related responses, notably through suppression of the antioxidant transporter SLC7A11 (–2.60). The APB+Dex treatment synergistically targeted multiple tumour-promoting mechanisms, including the impairment of redox homeostasis through SLC7A11 suppression, and inhibition of the haemostasis, platelet activation network and NF-κB signalling pathway via downregulation of NFKB1 (–1.34), exemplified by increased expression of SERPINE1 (1.99) within the “response to elevated platelet cytosolic Ca²⁺” pathway. These findings underscored a multifaceted anticancer mechanism by APB+Dex that may collectively impair cell proliferation, survival signalling, immune modulation, and tumour microenvironment support.