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Background <p>Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent type of chronic liver disease, posing a significant threat to human health. Protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) plays a pivotal role in regulating metabolic diseases. Nevertheless, the underlying molecular mechanisms by which PRKAA2 influences the pathogenesis of MASLD remain unclear.</p> Method <p>Bioinformatics analysis of public datasets identified the potential role of PRKAA2 in MASLD, verified its immune cells correlation, and constructed its competitive endogenous RNA (ceRNA) network. We assessed the mRNA and protein expression of PRKAA2, along with phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) phosphorylation levels after PRKAA2 knockdown. Pro-inflammatory cytokines were quantified by Enzyme-linked immunosorbent assay (ELISA), and lipid species were profiled using Liquid chromatography-mass spectrometry (LC-MS). In vivo, hepatic morphology and lipid deposition were evaluated by Hematoxylin-eosin (H&amp;E) staining. Immunofluorescence measured PRKAA2, phospho-PI3K (p-PI3K) and phospho-AKT (p-AKT) expression. The regulatory interaction between PRKAA2 and its upstream miRNA was confirmed by dual-luciferase reporter assay.</p> Results <p>Our bioinformatics analysis identified PRKAA2 as a significantly upregulated gene in MASLD. Both in vitro and in vivo experiments consistently revealed markedly elevated PRKAA2 expression levels in MASLD models. Knockdown of PRKAA2 significantly reduced lipid accumulation, suppressed production of pro-inflammatory cytokines and attenuated the phosphorylation ratios of PI3K and AKT. Further mechanistic investigations confirmed that hsa-let-7b-5p directly targets PRKAA2 by binding to its wild-type (WT) 3’UTR, establishing this miRNA as a key upstream regulator of PRKAA2 in MASLD pathogenesis.</p> Conclusions <p>Our findings collectively demonstrated that PRKAA2 serves as a crucial mediator in MASLD pathogenesis, functioning through a novel regulatory axis involving the upstream hsa-let-7b-5p and the downstream activation of the PI3K/AKT pathway.</p>

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PRKAA2 mediates the pathogenesis of metabolic dysfunction-associated steatotic liver disease via PI3K/AKT signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • Jiayi Li,
  • Guiling Wu,
  • Zihao Li,
  • Xinghuan Liang,
  • Yiyu Chen,
  • Bing Yang,
  • Jing Xian,
  • Tingting Deng,
  • Cuihong Chen,
  • Li Li,
  • Yang Liu,
  • Tian Xiong,
  • Sihui Wu,
  • Xi Yang,
  • Yingfen Qin

摘要

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent type of chronic liver disease, posing a significant threat to human health. Protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) plays a pivotal role in regulating metabolic diseases. Nevertheless, the underlying molecular mechanisms by which PRKAA2 influences the pathogenesis of MASLD remain unclear.

Method

Bioinformatics analysis of public datasets identified the potential role of PRKAA2 in MASLD, verified its immune cells correlation, and constructed its competitive endogenous RNA (ceRNA) network. We assessed the mRNA and protein expression of PRKAA2, along with phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) phosphorylation levels after PRKAA2 knockdown. Pro-inflammatory cytokines were quantified by Enzyme-linked immunosorbent assay (ELISA), and lipid species were profiled using Liquid chromatography-mass spectrometry (LC-MS). In vivo, hepatic morphology and lipid deposition were evaluated by Hematoxylin-eosin (H&E) staining. Immunofluorescence measured PRKAA2, phospho-PI3K (p-PI3K) and phospho-AKT (p-AKT) expression. The regulatory interaction between PRKAA2 and its upstream miRNA was confirmed by dual-luciferase reporter assay.

Results

Our bioinformatics analysis identified PRKAA2 as a significantly upregulated gene in MASLD. Both in vitro and in vivo experiments consistently revealed markedly elevated PRKAA2 expression levels in MASLD models. Knockdown of PRKAA2 significantly reduced lipid accumulation, suppressed production of pro-inflammatory cytokines and attenuated the phosphorylation ratios of PI3K and AKT. Further mechanistic investigations confirmed that hsa-let-7b-5p directly targets PRKAA2 by binding to its wild-type (WT) 3’UTR, establishing this miRNA as a key upstream regulator of PRKAA2 in MASLD pathogenesis.

Conclusions

Our findings collectively demonstrated that PRKAA2 serves as a crucial mediator in MASLD pathogenesis, functioning through a novel regulatory axis involving the upstream hsa-let-7b-5p and the downstream activation of the PI3K/AKT pathway.