Despite notable advancements in the investigation and management of lung adenocarcinoma (LUAD), the mortality rate for individuals afflicted with LUAD remains elevated, and attaining an accurate prognosis is challenging. LUAD exhibits intricate genetic and environmental components, and it is plausible that free fatty acid receptors (FFARs) may bridge the genetic and dietary aspects. The objective of this study is to ascertain whether a correlation exists between FFAR4, which functions as the primary receptor for dietary fatty acids, and various characteristics of LUAD, while also delving into the potential underlying mechanism. The findings of this study indicate a decrease in FFAR4 expression in LUAD, with a positive correlation (P < 0.01) between FFAR4 levels and overall patient survival (OS). Receiver operating characteristic (ROC) curve analysis demonstrated a significant diagnostic value [area under the curve (AUC) of 0.933] associated with FFAR4 expression. Functional investigations revealed that the FFAR4-specific agonist (TUG891) effectively suppressed cell proliferation and induced cell cycle arrest. Furthermore, FFAR4 activation resulted in significant metabolic shifts, including a decrease in oxygen consumption rate (OCR) and an increase in extracellular acidification rate (ECAR) in A549 cells. In detail, the activation of FFAR4 has been observed to impact the assembly process of the mitochondrial respiratory chain complex and the malate–aspartate shuttle process, resulting in a decrease in the transition of NAD+ to NADH and the inhibition of LUAD. These discoveries reveal a previously unrecognized function of FFAR4 in the negative regulation of mitochondrial metabolism and the inhibition of LUAD, indicating its potential as a promising therapeutic target for the treatment and diagnosis of LUAD.

中文翻译：

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FFAR4 激活通过阻断呼吸链复合物组装相关的线粒体代谢抑制肺腺癌

尽管肺腺癌 (LUAD) 的研究和治疗取得了显着进展，但 LUAD 患者的死亡率仍然很高，并且获得准确的预后具有挑战性。LUAD 表现出复杂的遗传和环境因素，游离脂肪酸受体 (FFAR) 可能会在遗传和饮食方面发挥桥梁作用。本研究的目的是确定作为膳食脂肪酸主要受体的 FFAR4 与 LUAD 的各种特征之间是否存在相关性，同时深入探讨潜在的潜在机制。本研究的结果表明 LUAD 中 FFAR4 表达下降，FFAR4 水平与患者总生存期 (OS) 呈正相关 (P < 0.01)。受试者工作特征 (ROC) 曲线分析证明与 FFAR4 表达相关的显着诊断价值 [曲线下面积 (AUC) 为 0.933]。功能研究表明，FFAR4 特异性激动剂 (TUG891) 能有效抑制细胞增殖并诱导细胞周期停滞。此外，FFAR4 激活导致显着的代谢变化，包括 A549 细胞中耗氧率 (OCR) 的降低和细胞外酸化率 (ECAR) 的增加。详细而言，已观察到 FFAR4 的激活会影响线粒体呼吸链复合物的组装过程和苹果酸-天冬氨酸穿梭过程，导致 NAD+ 向 NADH 的转变减少并抑制 LUAD。这些发现揭示了 FFAR4 在线粒体代谢负调节和 LUAD 抑制中的先前未被认识的功能，表明其作为治疗和诊断 LUAD 的有前途的治疗靶点的潜力。