Abstract：
Obesity is closely related to a poor prognosis in patients with advanced colorectal cancer (CRC), but the mechanisms remain unclear. Ferroptosis is a form of nonapoptotic cell death characterized by lipid reactive oxygen species (ROS) accumulation and iron dependency and is associated with the chemoresistance of tumors. Here, it is shown that adipose-derived exosomes reduce ferroptosis susceptibility in CRC, thus promoting chemoresistance to oxaliplatin. It is found that microsomal triglyceride transfer protein (MTTP) expression is increased in the plasma exosomes of CRC patients with a high body fat ratio, serving as an inhibitor of ferroptosis and reducing sensitivity to chemotherapy. Mechanistically, the MTTP/proline-rich acidic protein 1 (PRAP1) complex inhibited zinc finger E-box binding homeobox 1 expression and upregulated glutathione peroxidase 4 and xCT, leading to a decreased polyunsaturated fatty acids ratio and lipid ROS levels. Moreover, experiments are carried out in organoids, and a tumor implantation model is established in obese mice, demonstrating that the inhibition of MTTP increases the sensitivity to chemotherapy. The results reveal a novel intracellular signaling pathway mediated by adipose-derived exosomes and suggest that treatments targeting secreted MTTP might reverse oxaliplatin resistance in CRC.
摘要：
肥胖与晚期结直肠癌(CRC)患者的不良预后密切相关。但机制尚不清楚。铁凋亡是非凋亡性细胞死亡的一种形式，其特征在于脂质活性氧（ROS）积累和铁依赖性，并且与肿瘤的化学抗性有关。这里,它表明，脂肪来源的外泌体减少铁凋亡易感性在CRC，从而促进对奥沙利铂的化学抗性。发现微粒体甘油三酯转移蛋白（MTTP）在高体脂比的CRC患者血浆外泌体中表达增加，作为铁凋亡的抑制剂，降低对化疗的敏感性。机械上,MTTP/富含脯氨酸的酸性蛋白1（PRAP1）复合物抑制锌指E盒结合同源盒1的表达，并上调谷胱甘肽过氧化物酶4和xCT，导致多不饱和脂肪酸比例和脂质ROS水平降低。此外，实验是在类器官中进行的，并在肥胖小鼠中建立肿瘤植入模型，证明抑制MTTP增加了对化疗的敏感性。结果揭示了由脂肪来源的外泌体介导的新的细胞内信号通路，并表明靶向分泌的MTTP的治疗可能逆转CRC中的奥沙利铂耐药。
