结直肠癌 (CRC) 是第三大诊断最多、死亡率最高的恶性肿瘤，在全世界范围内带来严重的健康问题。寻找有效治疗结直肠癌的方法具有挑战性，并引起严重关切。山奈酚是一种有效的抗癌生物活性化合物，通常被建议用于治疗各种癌症，包括结直肠癌。然而，其对抗结直肠癌的潜在分子机制仍不清楚。本研究深入研究了山奈酚的分子途径和针对 CRC 靶标的潜在分子机制。检索了山奈酚的目标蛋白编码基因，并筛选了 CRC 相关基因。验证了疾病特异性指数≥0.6的12个常见靶点在CRC不同阶段的蛋白表达。选择过表达的USP1、SETD7、POLH、TDP1和RACGAP1进行进一步研究。使用分子对接和分子动力学（MD）模拟评估山奈酚与相应蛋白质的结合亲和力。 SETD7 表现出最高的结合亲和力和最低的结合能（- 8.06 kcal/mol）。此外，MD模拟和MM-PBSA赋予SETD7-山奈酚复合物具有最小的均方根偏差、较低的相互作用能和较高的构象稳定性。构建的 SETD7 的蛋白质-蛋白质相互作用揭示了直接相互作用因子，即 DNMT1、FOXO1、FOXO3、FOXO4、H3-3B、H3-4、H3C12、H3C13、SETD7、SIRT1 和 TP53，通过 FOXO 信号传导在癌症进展中具有潜在作用。总之，我们的研究揭示了山奈酚对多个CRC靶点的多靶点和协同作用及其潜在机制。最后，该研究建议进行体外和体内试验来验证 CRC 的抗癌药物。© 2024。作者获得 Springer Nature Switzerland AG 的独家许可。

Colorectal cancer (CRC) is the third most diagnosed and highly fatal malignancy, presenting serious health concerns worldwide. The search for an effective cure for CRC is challenging and poses a serious concern. Kaempferol is a potent anti-cancerous bioactive compound often suggested for treating various cancers, including CRC. However, its underlying molecular mechanism against CRC remains unclear. The present study delves into kaempferol's molecular pathways and underlying molecular mechanisms against CRC targets. The target protein-coding genes for kaempferol were retrieved, and the CRC-associated genes were curated. Twelve common targets with a disease specificity index of > 0.6 were validated for their protein expression at different stages of CRC. Over-expressed USP1, SETD7, POLH, TDP1 and RACGAP1 were selected for further studies. The binding affinities of kaempferol to the corresponding proteins were evaluated using molecular docking and Molecular Dynamics (MD) simulations. SETD7 exhibited the highest binding affinity with the lowest binding energy (- 8.06 kcal/mol). Additionally, the MD simulation, and MM-PBSA conferred SETD7-kaempferol complex had the least root-mean-square deviation with lower interaction energy and higher conformational stability. The protein-protein interaction of SETD7 constructed revealed direct interactors, namely, DNMT1, FOXO1, FOXO3, FOXO4, H3-3B, H3-4, H3C12, H3C13, SETD7, SIRT1 and TP53, have a potential role in cancer progression through FOXO signalling. In summary, our study revealed kaempferol's multi-target and synergistic effect on multiple CRC targets and its underlying mechanisms. Finally, the study recommends in-vitro and in-vivo trials for validation of anti-cancerous drugs for CRC.© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.