需要新的治疗方法来改善肺癌（LC）的预后，肺癌是全球癌症相关死亡的主要原因。在中国广泛使用的中草药配方为改善肺癌治疗提供了独特的机会，双黄升白（SHSB）方剂是一个典型的例子。然而，其作用机制仍不清楚。本研究旨在确认 SHSB 对肺腺癌（LUAD）的疗效（LUAD 是 LC 的主要组织学类型），揭示该配方的下游靶点，并评估新发现靶点的临床相关性和生物学作用。使用实验性转移小鼠模型和皮下移植小鼠模型评估 SHSB 的抗癌活性。进行亚细胞瘤和血清代谢组学分析，以识别 SHSB 的下游靶点，特别是代谢靶点。开展临床试验验证新发现的代谢靶点。然后，在临床样本中测量参与 SHSB 靶向的代谢途径的代谢产物和酶。最后，进行常规分子实验以解析 SHSB 靶向的代谢途径的生物学功能。口服 SHSB 显示出显著的抗 LUAD 疗效，如转移模型的延长总生存期和皮下移植模型肿瘤的生长受损。机制上，SHSB 处理改变了后转录层的蛋白质表达，并且修饰了 LUAD 移植瘤的代谢组。整合分析表明，SHSB 在肿瘤中通过后转录下调 ATP-柠檬酸裂解酶（ACLY），显著抑制乙酰辅酶 A 的合成。一致地，我们的临床试验显示，口服 SHSB 处理降低了肺癌患者血清中的乙酰辅酶 A 水平。此外，在临床的 LUAD 组织中，乙酰辅酶 A 合成和 ACLY 表达都增加了，并且高的肿瘤内 ACLY 表达预示着不良的预后。最后，我们表明，由 ACLY 介导的乙酰辅酶 A 合成对于 LUAD 细胞的生长是必不可少的，通过促进 G1/S 转化和 DNA 复制。先前的假设驱动的研究中报道了 SHSB 的有限下游靶点，本研究进行了全面的多组学调查，并证明 SHSB 通过调节蛋白质表达和特别抑制 ACLY 介导的乙酰辅酶 A 合成来发挥其抗 LUAD 的功效。Copyright © 2023 The Authors. Published by Elsevier GmbH. All rights reserved.

New therapeutic approaches are required to improve the outcomes of lung cancer (LC), a leading cause of cancer-related deaths worldwide. Chinese herbal medicine formulae widely used in China provide a unique opportunity for improving LC treatment, and the Shuang-Huang-Sheng-Bai (SHSB) formula is a typical example. However, the underlying mechanisms of action remains unclear.This study aimed to confirm the efficacy of SHSB against lung adenocarcinoma (LUAD), which is a major histological type of LC, unveil the downstream targets of this formula, and assess the clinical relevance and biological roles of the newly identified target.An experimental metastasis mouse model and a subcutaneous xenograft mouse model were used to evaluate the anti-cancer activity of SHSB. Multi-omics profiling of subcutaneous tumors and metabolomic profiling of sera were performed to identify downstream targets, especially the metabolic targets of SHSB. A clinical trial was conducted to verify the newly identified metabolic targets in patients. Next, the metabolites and enzymes engaged in the metabolic pathway targeted by SHSB were measured in clinical samples. Finally, routine molecular experiments were performed to decipher the biological functions of the metabolic pathways targeted by SHSB.Oral SHSB administration showed overt anti-LUAD efficacy as revealed by the extended overall survival of the metastasis model and impaired growth of implanted tumors in the subcutaneous xenograft model. Mechanistically, SHSB administration altered protein expression in the post-transcriptional layer and modified the metabolome of LUAD xenografts. Integrative analysis demonstrated that SHSB markedly inhibited acetyl-CoA synthesis in tumors by post-transcriptionally downregulating ATP-citrate lyase (ACLY). Consistently, our clinical trial showed that oral SHSB administration declined serum acetyl-CoA levels of patients with LC. Moreover, acetyl-CoA synthesis and ACLY expression were both augmented in clinical LUAD tissues of patients, and high intratumoral ACLY expression predicted a detrimental prognosis. Finally, we showed that ACLY-mediated acetyl-CoA synthesis is essential for LUAD cell growth by promoting G1/S transition and DNA replication.Limited downstream targets of SHSB for LC treatment have been reported in previous hypothesis-driven studies. In this study, we conducted a comprehensive multi-omics investigation and demonstrated that SHSB exerted its anti-LUAD efficacy by actively and post-transcriptionally modulating protein expression and particularly restraining ACLY-mediated acetyl-CoA synthesis.Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.