畸变的肿瘤代谢是癌症的标志，其中代谢重塑可以支持在营养不足条件下的肿瘤生长。KRAS突变在所有结肠癌（CRC）病例的35-45％中发生，并且很难治疗。突变KRAS与CRC中的畸变代谢之间的关系尚未完全探索，但可能是干预的目标。我们之前从I-III期化疗纯种CRC患者的161个肿瘤组织和39个正常结肠组织获取了非定向代谢组学数据。在本研究中，我们揭示了仅在男性患者中，具有KRAS突变的肿瘤具有抑制铁死亡的几个改变的途径，包括谷胱甘肽生物合成、转硫酸作用和甲硫氨酸代谢。为了验证这种表型，将MC38 CRC细胞（KRASG13R）用铁死亡诱导剂RAS-selected lethal (RSL3)处理了。RSL3改变了代谢途径，与男性患者中KRAS突变肿瘤中所见到的方向相反，从而证实了这些患者中抑制铁死亡的代谢表型。我们进一步验证了来自另一个CRC患者队列(Gene Expression Omnibus (GEO))的基因表达数据，并观察到不同性别和KRAS状态的铁死亡相关基因。对这些基因与GEO队列中的总生存率(OS)之间关系的进一步检查显示，与KRAS野生型肿瘤相比，KRAS突变肿瘤与男性患者的5年OS更差。此外，与抑制铁死亡的GPX4、FTH1、FTL的低表达相比，KRAS突变肿瘤中这些基因的高表达与男性CRC患者的5年OS更差相关。此外，与ACS L4高表达相比，其低表达与该组的更差OS相关。我们的结果表明，男性CRC患者的KRAS突变肿瘤具有抑制铁死亡，并且抑制铁死亡的基因表达变化与这些患者的不良预后相关，揭示了一种新的潜在治疗途径。 版权所有 © 2023 The Authors。由Elsevier B.V. 发布，保留所有权利。

Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that only in male patients, tumors with KRAS mutations had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO)), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL, which suppress ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Additionally, low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.