采用多维方法解析与乳酰化相关的特征在结直肠癌预后和治疗中的复杂性。

BACKGROUND: Lactylation, a novel contributor to post-translational protein modifications, exhibits dysregulation across various tumors. Nevertheless, its intricate involvement in colorectal carcinoma, particularly for non-histone lactylation and its intersection with metabolism and immune evasion, remains enigmatic. METHODS: Employing immunohistochemistry on tissue microarray with clinical information and immunofluorescence on colorectal cell lines, we investigated the presence of global lactylation and its association with development and progression in colorectal cancer as well as its functional location. Leveraging the AUCell algorithm alongside correlation analysis in single-cell RNA sequencing data, as well as cox-regression and lasso-regression analysis in TCGA dataset and confirmed in GEO dataset, we identified a 23-gene signature predicting colorectal cancer prognosis. Subsequently, we analyzed the associations between the lactylation related gene risk and clinical characteristics, mutation landscapes, biological functions, immune cell infiltration, immunotherapy responses, and drug sensitivity. Core genes were further explored for deep biological insights through bioinformatics and in vitro experiments. RESULTS: Our study innovatively reveals a significant elevation of global lactylation in colorectal cancer, particularly in malignant tumors, confirming it as an independent prognostic factor for CRC. Through a comprehensive analysis integrating tumor tissue arrays, TCGA dataset, GEO dataset, combining in silico investigations and in vitro experiments, we identified a 23-gene Lactylation-Related Gene risk model capable of predicting the prognosis of colorectal cancer patients. Noteworthy variations were observed in clinical characteristics, biological functions, immune cell infiltration, immune checkpoint expression, immunotherapy responses and drug sensitivity among distinct risk groups. CONCLUSIONS: The Lactylation-Related Gene risk model exhibits significant potential for improving the management of colorectal cancer patients and enhancing therapeutic outcomes, particularly at the intersection of metabolism and immune evasion. This finding underscores the clinical relevance of global lactylation in CRC and lays the groundwork for mechanism investigation and targeted therapeutic strategies given the high lactate concentration in CRC.

背景：乳酰化作用，一种新的翻译后蛋白质修饰方式，在各种肿瘤中都存在失调现象。然而，它在结直肠癌中的复杂作用，特别是非组蛋白乳酰化作用及其与代谢和免疫逃逸的相互作用，仍然是个谜。

方法：我们使用组织微阵列的免疫组织化学和结直肠细胞系的免疫荧光技术，研究了全局乳酰化作用在结直肠癌发生和发展中的存在及其与发展和进展的关系，以及其功能位置。利用单细胞 RNA 测序数据中的 AUCell 算法和相关性分析，以及 TCGA 数据集和 GEO 数据集的 cox 回归和lasso 回归分析，我们确定了一个预测结直肠癌预后的 23 基因特征。随后，我们分析了乳酰化相关基因风险与临床特征、突变景观、生物学功能、免疫细胞浸润、免疫治疗反应和药物敏感性之间的关联。通过生物信息学和体外实验，对核心基因进行了深入的生物学研究。

结果：我们的研究创新性地揭示了结直肠癌中全局乳酰化作用的显著升高，特别是在恶性肿瘤中，证实其是 CRC 的独立预后因素。通过综合分析肿瘤组织阵列、TCGA 数据集、GEO 数据集，结合计算机研究和体外实验，我们确定了一个 23 基因乳酰化相关基因风险模型，能够预测结直肠癌患者的预后。在不同风险组中，临床特征、生物学功能、免疫细胞浸润、免疫检查点表达、免疫治疗反应和药物敏感性均有显著差异。

结论：乳酰化相关基因风险模型在改善结直肠癌患者管理和提高治疗效果方面具有显著潜力，特别是在代谢和免疫逃逸的交叉点。鉴于结直肠癌中高浓度的乳酸，这一发现突显了全局乳酰化作用在 CRC 中的临床相关性，并为机制研究和靶向治疗策略奠定了基础。