2. Academic Validation
  3. Linarin alleviates high-fat diet-induced hepatic steatosis by inhibiting PDE4D and activating the cAMP/PKA/CREB pathway

Linarin alleviates high-fat diet-induced hepatic steatosis by inhibiting PDE4D and activating the cAMP/PKA/CREB pathway

  • Free Radic Biol Med. 2025 Nov:239:116-129. doi: 10.1016/j.freeradbiomed.2025.07.030.
Yang Xiao 1,  Jiale Wang 1,  Hao Zhang 1,  Xingzhen Yang 1,  Jinfeng Zhou 1,  Yunpeng Zhou 2,  Siqi Liu 3,  Mengkuan Liu 1,  Yi Wang 2,  Yang Wang 1,  Qichao Liao 1,  Menglong Hou 3,  Yi Hao 2,  Shi Liu 3,  Zupeng Luo 3,  Shuang Zhang 1,  Jingsu Yu 3,  Lin Yu 3,  Lei Zhou 4,  Yixing Li 5,  Gaopeng Li 6
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China.
  • 2 Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China.
  • 3 Institute of Digestive Disease, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China.
  • 4 Institute of Digestive Disease, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China. Electronic address: lzhou@gxams.org.cn.
  • 5 Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China. Electronic address: liyixing39@gxu.edu.cn.
  • 6 Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China. Electronic address: malone2001@163.com.
PMID: 40712988 DOI: 10.1016/j.freeradbiomed.2025.07.030
Abstract

Metabolic-associated fatty liver disease (MAFLD), a major consequence of obesity and metabolic dysfunction, lacks effective treatments. The cAMP/PKA signaling pathway regulates lipid metabolism, and inhibition of its upstream target PDE4D alleviates MAFLD progression. Linarin, a natural flavonoid glycoside with hepatoprotective properties, remains underexplored for MAFLD mechanisms. To investigate linarin's therapeutic effects on high-fat diet (HFD)-induced MAFLD and elucidate its mechanisms, focusing on PDE4D inhibition and cAMP/PKA/CREB pathway activation. C57BL/6J mice were fed a normal diet (CON), high fat diet (HFD), HFD + 50 mg/kg linarin, and HFD + 100 mg/kg linarin. Oleic/palmitic acid-stimulated HepG2, Mouse primary cells and AML12 cells were used. In vitro, 25 μM linarin reduced intracellular triglycerides (TG), elevated ATP production, decreased ROS and MDA, and upregulated GSH and CAT. In vivo, 50 and 100 mg/kg linarin suppressed weight gain, reduced hepatic fat deposition, and improved Insulin sensitivity and liver function. Mechanistically, linarin inhibits PDE4D activity, activates the cAMP/PKA/CREB pathway, and upregulates GPX4 expression. Linarin alleviates MAFLD by targeting PDE4D to activate the cAMP/PKA/CREB pathway, improving lipid metabolism, mitochondrial function, and oxidative stress. This study highlights the potential of natural compounds for Metabolic Disease intervention, providing a foundation for clinical translation.

Keywords

Fatty liver; Linarin; Lipid metabolism; Obesity; Phosphodiesterase 4D (PDE4D).

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