Zhao Xiaomei, Xiao Yangfan, Jiang Miao, Cao Yi
Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, China.
Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, China.
Mol Biol Rep. 2025 May 26;52(1):506. doi: 10.1007/s11033-025-10613-0.
Kruppel-like factors (KLFs) are transcription factors (TFs) increasingly implicated in cardiovascular pharmacology and toxicology through molecular mechanisms regulating endothelial function, macrophage polarization, and lipid metabolism. For example, KLF2/4 maintains endothelial homeostasis by modulating endothelial nitric oxide synthase (eNOS) activity and oxidative stress, and KLF4 additionally regulates smooth muscle cell phenotypic switch. KLF6 governs macrophage polarization and pyroptosis, while KLF15 modulates cardiomyocyte lipid metabolism, with dysregulation linked to cardiomyopathy. Not surprisingly, drugs such as statins and phytochemicals, as well as toxicants like ox-LDL, nanomaterials, and radiation, alter KLF expression via non-coding RNA (such as microRNA) or TFs, influencing endothelial cell activation, vascular smooth muscle cell phenotypic switch, macrophage inflammation, and cardiomyocyte apoptosis. KLF-dependent pathways intersect with key toxicological processes, such as autophagy, ferroptosis, and lipid dysregulation, culminating in atherosclerosis and heart failure. Despite preclinical advances demonstrating KLFs as therapeutic targets, clinical translation remains limited, with no KLF-targeted agents in active trials. Future studies should delineate tissue-specific KLF interactions, resolve KLFs' conflicting roles, and explore CRISPR-based KLF-targeting modulation. Bridging molecular mechanisms, such as KLF's regulation of phenotypic transformation pathways in smooth muscle cells, to drug discovery could yield novel therapies for cardiovascular diseases. The present review underscores the need for mechanistic and translational research to harness KLFs in cardiovascular pharmacotherapy and toxicant risk assessment.
Kruppel样因子（KLFs）是转录因子（TFs），通过调节内皮功能、巨噬细胞极化和脂质代谢的分子机制，越来越多地参与心血管药理学和毒理学研究。例如，KLF2/4通过调节内皮型一氧化氮合酶（eNOS）活性和氧化应激来维持内皮稳态，KLF4还调节平滑肌细胞表型转换。KLF6控制巨噬细胞极化和焦亡，而KLF15调节心肌细胞脂质代谢，其失调与心肌病有关。不出所料，他汀类药物和植物化学物质等药物，以及氧化型低密度脂蛋白（ox-LDL）、纳米材料和辐射等毒物，通过非编码RNA（如微小RNA）或转录因子改变KLF表达，影响内皮细胞活化、血管平滑肌细胞表型转换、巨噬细胞炎症和心肌细胞凋亡。KLF依赖的信号通路与关键的毒理学过程相互交织，如自噬、铁死亡和脂质失调，最终导致动脉粥样硬化和心力衰竭。尽管临床前研究进展表明KLFs可作为治疗靶点，但临床转化仍然有限，目前尚无针对KLF的药物在进行临床试验。未来的研究应明确组织特异性的KLF相互作用，解决KLF的矛盾作用，并探索基于CRISPR的KLF靶向调节。将分子机制，如KLF对平滑肌细胞表型转化途径的调节，与药物发现联系起来，可能会产生治疗心血管疾病的新疗法。本综述强调了在心血管药物治疗和毒物风险评估中，开展机制和转化研究以利用KLFs的必要性。
