2. Academic Validation
  3. Krüppel-like factor 15 ameliorates alcohol-induced liver injury in mice via regulation of the PFKFB3/AKT axis

Krüppel-like factor 15 ameliorates alcohol-induced liver injury in mice via regulation of the PFKFB3/AKT axis

  • Acta Pharmacol Sin. 2025 Sep 11. doi: 10.1038/s41401-025-01651-2.
Hao Chen # 1 2,  Lin Yang # 3,  Xiao-Feng Li # 3,  Si-Yuan Han 3,  Qi Zhao 3,  Rong-Cheng Xiao 3,  Zi-Yao Ou 3,  Ling Fang 4 5 6,  Yan Du 7 8 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 2 The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, China.
  • 3 School of Pharmaceutical Sciences, Anhui Medical University, Hefei, 230032, China.
  • 4 Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. fangling@ahmu.edu.cn.
  • 5 The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, China. fangling@ahmu.edu.cn.
  • 6 School of Pharmaceutical Sciences, Anhui Medical University, Hefei, 230032, China. fangling@ahmu.edu.cn.
  • 7 Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. duyan1206@163.com.
  • 8 The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, China. duyan1206@163.com.
  • 9 School of Pharmaceutical Sciences, Anhui Medical University, Hefei, 230032, China. duyan1206@163.com.
  • # Contributed equally.
PMID: 40935894 DOI: 10.1038/s41401-025-01651-2
Abstract

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.

Keywords

KLF15; PI3K/AKT; alcohol-induced liver disease; apoptosis; inflammation; steatosis.

Figures
Products