Chen Hao, Yang Lin, Li Xiao-Feng, Han Si-Yuan, Zhao Qi, Xiao Rong-Cheng, Ou Zi-Yao, Fang Ling, Du Yan
Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, China.
Acta Pharmacol Sin. 2025 Sep 11. doi: 10.1038/s41401-025-01651-2.
Alcohol-associated liver disease (ALD) remains a predominant cause of chronic hepatic pathology, and effective therapeutic strategies are needed. Krüppel-like factor 15 (KLF15) is a member of the KLF family of zinc-finger transcription factors and is ubiquitously expressed in metabolically active tissues, with a particularly high abundance in the liver. KLF15 has been implicated in various hepatic disorders. In this study, we investigated the pathophysiological role of KLF15 in ALD. We established a National Institute on Alcohol Abuse and Alcoholism (NIAAA) model in mice by feeding them an ethanol Lieber-DeCarli liquid diet containing 5% (vol/vol) ethanol for 10 days. EtOH-fed mice were administered binge ethanol gavage (5 g/kg, body weight) on D11. We observed that the expression levels of KLF15 were significantly decreased in the livers of ALD patients and model mice. Overexpression of KLF15 conferred substantial protective effects in EtOH-fed mice, as evidenced by attenuated hepatic injury, apoptosis, steatosis and inflammation. In ethanol-treated AML-12 cells, overexpression of KLF15 reduced apoptosis and steatosis, whereas KLF15 knockdown exacerbated these pathological features. By performing RNA-seq and bioinformatics analyses, we observed that KLF15 regulated the AKT pathway by directly binding to the PFKFB3 promoter (-128 to -121). The physical interaction between PFKFB3 and AKT1 was further verified by Co-IP and molecular docking. These results suggest that KLF15 is a pivotal regulator of ALD pathogenesis through modulation of the PFKFB3/AKT axis, highlighting its potential as a novel therapeutic target for ALD intervention.
酒精性肝病（ALD）仍然是慢性肝脏病理的主要原因，因此需要有效的治疗策略。Krüppel样因子15（KLF15）是锌指转录因子KLF家族的成员，在代谢活跃的组织中普遍表达，在肝脏中含量特别高。KLF15与多种肝脏疾病有关。在本研究中，我们调查了KLF15在ALD中的病理生理作用。我们通过给小鼠喂食含5%（体积/体积）乙醇的乙醇Lieber-DeCarli液体饮食10天，建立了美国国立酒精滥用与酒精中毒研究所（NIAAA）小鼠模型。在第11天，给喂食乙醇的小鼠进行一次性乙醇灌胃（5克/千克体重）。我们观察到ALD患者和模型小鼠肝脏中KLF15的表达水平显著降低。KLF15的过表达在喂食乙醇的小鼠中具有显著的保护作用，肝损伤、细胞凋亡、脂肪变性和炎症减轻证明了这一点。在乙醇处理的AML-12细胞中，KLF15的过表达减少了细胞凋亡和脂肪变性，而KLF15的敲低加剧了这些病理特征。通过进行RNA测序和生物信息学分析，我们观察到KLF15通过直接结合PFKFB3启动子（-128至-121）来调节AKT通路。通过免疫共沉淀和分子对接进一步验证了PFKFB3与AKT1之间的物理相互作用。这些结果表明，KLF15通过调节PFKFB3/AKT轴是ALD发病机制的关键调节因子，突出了其作为ALD干预新治疗靶点的潜力。
