The role of PI3k/AKT signaling pathway in attenuating liver fibrosis: a comprehensive review

Abstract

Excessive accumulation of extracellular matrix (ECM) components within the liver leads to a pathological condition known as liver fibrosis. Alcohol abuse, non-alcoholic fatty liver disease (NAFLD), autoimmune issues, and viral hepatitis cause chronic liver injury. Exploring potential therapeutic targets and understanding the molecular mechanisms involved in liver fibrosis are essential for the development of effective interventions. The goal of this comprehensive review is to explain how the PI3K/AKT signaling pathway contributes to the reduction of liver fibrosis. The potential of this pathway as a therapeutic target is investigated through a summary of results from in vivo and in vitro studies. Studies focusing on PI3K/AKT activation have shown a significant decrease in fibrosis markers and a significant improvement in liver function. The review emphasizes how this pathway may prevent ECM synthesis and hepatic stellate cell (HSC) activation, ultimately reducing the fibrotic response. The specific mechanisms and downstream effectors of the PI3K/AKT pathway in liver fibrosis constitute a rapidly developing field of study. In conclusion, the PI3K/AKT signaling pathway plays a significant role in attenuating liver fibrosis. Its complex role in regulating HSC activation and ECM production, demonstrated both in vitro and in vivo, underscores its potential as a effective therapeutic approach for managing liver fibrosis and slowing disease progression. A comprehensive review of this field provides valuable insights into its future developments and implications for clinical applications.

Keywords: PI3K/Akt pathway; attenuating liver fibrosis; extracellular matrix; hepatic stellate cells; liver fibrosis.

Figure 1

Growth factors and hormones activate receptor tyrosine kinases (RTKs) on the cell membrane. RTK activation initiates the activation of PI3K. PI3K converts PIP2 into PIP3. PIP3 recruits AKT to the cell membrane. AKT is phosphorylated and activated by PDK1 and mTORC2. AKT phosphorylates various downstream effectors. GSK3β, Inhibition of GSK3β stabilizes β-catenin, leading to downregulation of ECM synthesis. This cascade regulates cell survival, growth, protein synthesis, glucose homeostasis, and angiogenesis. SOCS and IRS are key regulators in preventing excessive activation of the PI3K/AKT pathway.

Figure 2

This diagram shows AKT/PI3K function, (1) Cell development regulation: AKT pathway regulates cell development by stimulating protein synthesis and inhibiting apoptosis through the phosphorylation of pro-apoptotic proteins like Bad and caspase-9, promotes cell development, (2) glucose homeostasis: AKT activation facilitates glucose homeostasis by enhancing glucose utilization and absorption, ensuring ample energy for cellular functions, and preventing glycogen breakdown, (3) cell proliferation and protein synthesis: AKT promotes cell proliferation and protein synthesis by activating mTORC1, which phosphorylates key effectors (S6K and 4E-BP1), promoting cell growth. AKT activation advances the cell cycle by blocking inhibitors (p21 and p27), permitting cell division, and (4) angiogenesis control: AKT/PI3K pathway controls angiogenesis by stimulating VEGF synthesis, promoting endothelial cell migration and proliferation for the formation of new blood vessels. Essential for tissue repair, growth, and efficient transport of nutrients and oxygen to tissues.

Figure 3

This diagram illustrates the mechanism of liver fibrosis, starting with the activation of PI3K, followed by the phosphorylation of PIP2 to generate PIP3, which activates PDK1 and mTORC2. Subsequently, AKT is activated at the plasma membrane by PDK1 and mTORC2. The PI3K/AKT signaling pathway exhibits a role in liver fibrosis, promoting the activation, proliferation, and excessive production of extracellular matrix (ECM) proteins in hepatic stellate cells (HSCs).

Figure 4

Mechanism of anti fibrotic effect in attenuating liver fibrosis. (1) Ant fibrotic effect decreases phosphorylation of Akt and FoxO1, which leads to FoxO1 nuclear translocation. This event leads to the upregulation of p21 and p27 protein expression, inducing G0/G1 phase arrest and subsequently inhibiting the proliferation of hepatic stellate cells (HSCs), (2) this diagram illustrates how the PI3K/AKT signaling pathway reduces liver fibrosis by inhibiting collagen, α-SMA, and HSC activation. The pathway’s activation leads to the inhibition of profibrogenic gene expression, possibly through NF-κB inhibition via AKT activation. AKT also regulates the TGF-β signaling pathway, inhibiting downstream effects and contributing to anti-fibrotic actions. The suppression of TGF-β signaling is highlighted as a key aspect of the pathway’s anti-fibrotic effects.