Colorectal cancer (CRC) is a common and deadly disease of the digestive system, but its targeted therapy is hampered by the lack of reliable and specific biomarkers. Hence, discovering new therapeutic targets and agents for CRC is an urgent and challenging task. Here we report that carnitine palmitoyltransferase 1A (CPT1A), a mitochondrial enzyme that catalyzes fatty acid oxidation (FAO), is a potential target for CRC treatment. We show that CPT1A is overexpressed in CRC cells and that its inhibition by a secolignan-type compound, 2,6-dihydroxypeperomin B (DHP-B), isolated from the plant Peperomia dindygulensis, suppresses tumor cell growth and induces apoptosis. We demonstrate that DHP-B covalently binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 interaction, leading to increased mitochondrial permeability and reduced oxygen consumption and energy metabolism in CRC cells. We also reveal that CPT1A expression correlates with the survival of tumor-bearing animals and that DHP-B exhibits anti-CRC activity in vitro and in vivo. Our study uncovers the molecular mechanism of DHP-B as a novel CPT1A inhibitor and provides a rationale for its preclinical development as well as a new strategy for CRC targeted therapy.

结直肠癌（CRC）是一种常见且致命的消化系统疾病，但其靶向治疗因缺乏可靠和特异性的生物标志物而受到阻碍。因此，发现结直肠癌的新治疗靶点和药物是一项紧迫且具有挑战性的任务。在这里，我们报道肉碱棕榈酰转移酶 1A (CPT1A) 是一种催化脂肪酸氧化 (FAO) 的线粒体酶，是 CRC 治疗的潜在靶点。我们发现 CPT1A 在 CRC 细胞中过度表达，并且从植物Peperomia dindygulensis中分离出的 secolignan 型化合物 2,6-二羟基胡椒明 B (DHP-B) 对其进行抑制，从而抑制肿瘤细胞生长并诱导细胞凋亡。我们证明DHP-B与CPT1A的Cys96共价结合，阻断FAO，并破坏线粒体CPT1A-VDAC1相互作用，导致CRC细胞中线粒体通透性增加、耗氧量和能量代谢减少。我们还揭示了 CPT1A 表达与荷瘤动物的存活相关，并且 DHP-B在体外和体内表现出抗 CRC 活性。我们的研究揭示了 DHP-B 作为新型 CPT1A 抑制剂的分子机制，为其临床前开发提供了理论依据，并为 CRC 靶向治疗提供了新策略。