Background:Short-chain fatty acids (SCFAs), microbial metabolites also known as postbiotics, are essential for maintaining gut health. However, their antiproliferative effects on gastric cancer cells and potential interactions with conventional therapies remain underexplored. This study aimed to investigate the effects of three SCFA salts—magnesium acetate (A), sodium propionate (P), and sodium butyrate (B)—individually and in combination (APB), as well as in combination with dexamethasone (Dex), on AGS gastric adenocarcinoma cells.Methods:AGS cells were treated with PB, AP, AB, APB, Dex, and APB+Dex. Cell viability was assessed to determine antiproliferative effects, and the IC50of APB was calculated. Flow cytometry was used to evaluate apoptosis and necrosis. Reactive oxygen species (ROS) levels were measured to assess oxidative stress. Proteomic analysis via LC-MS was performed to identify differential protein expression and related pathways impacted by the treatments.Results:SCFA salts showed significant antiproliferative effects on AGS cells, with APB exhibiting a combined IC50of 568.33 μg/mL. The APB+Dex combination demonstrated strong synergy (combination index = 0.76) and significantly enhanced growth inhibition. Both APB and APB+Dex induced substantial apoptosis (p< 0.0001) with minimal necrosis. APB alone significantly increased ROS levels (p< 0.0001), while Dex moderated this effect in the combination group APB+Dex (p< 0.0001). Notably, 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.Conclusions:These findings showed a multifaceted anticancer mechanism by APB+Dex that may collectively impair cell proliferation, survival signalling, immune modulation, and tumour microenvironment support in gastric cancer.
背景：短链脂肪酸（SCFAs）作为微生物代谢产物，亦被称为后生元，对维持肠道健康至关重要。然而，其对胃癌细胞的抗增殖作用及其与传统疗法的潜在相互作用仍未得到充分研究。本研究旨在探讨三种短链酸盐——乙酸镁（A）、丙酸钠（P）和丁酸钠（B）——单独使用、联合使用（APB）以及与地塞米松（Dex）联用对AGS胃腺癌细胞的影响。 方法：用PB、AP、AB、APB、Dex及APB+Dex处理AGS细胞。通过评估细胞活力确定抗增殖效应，并计算APB的半数抑制浓度（IC50）。采用流式细胞术评估细胞凋亡与坏死。测量活性氧（ROS）水平以评估氧化应激。通过液相色谱-质谱联用技术进行蛋白质组学分析，以鉴定差异表达的蛋白质及相关受影响的通路。 结果：短链酸盐对AGS细胞表现出显著的抗增殖作用，其中APB的联合IC50为568.33 μg/mL。APB+Dex组合显示出强烈的协同效应（联合指数=0.76），并显著增强了生长抑制。APB及APB+Dex均能诱导显著的细胞凋亡（p<0.0001），且坏死率极低。单独使用APB显著提高了ROS水平（p<0.0001），而Dex在APB+Dex组合中缓解了此效应（p<0.0001）。值得注意的是，APB+Dex治疗协同靶向了多种促癌机制，包括通过抑制SLC7A11破坏氧化还原稳态，以及通过下调NFKB1（−1.34）抑制止血、血小板活化网络和NF-κB信号通路，具体表现为在“响应血小板胞质Ca2+升高”通路中SERPINE1表达增加（1.99）。 结论：这些发现揭示了APB+Dex通过多层面的抗癌机制，可能共同削弱胃癌细胞的增殖、生存信号传导、免疫调节及肿瘤微环境支持。
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