Exploring the potential of treating chronic liver disease targeting the PI3K/Akt pathway and polarization mechanism of macrophages.

Chronic liver disease is a significant public health issue that can lead to considerable morbidity and mortality, imposing an enormous burden on healthcare resources. Understanding the mechanisms underlying chronic liver disease pathogenesis and developing effective treatment strategies are urgently needed. In this regard, the activation of liver resident macrophages, namely Kupffer cells, plays a vital role in liver inflammation and fibrosis. Macrophages display remarkable plasticity and can polarize into different phenotypes according to diverse microenvironmental stimuli. The polarization of macrophages into M1 pro-inflammatory or M2 anti-inflammatory phenotypes is regulated by complex signaling pathways such as the PI3K/Akt pathway. This review focuses on investigating the potential of using plant chemicals targeting the PI3K/Akt pathway for treating chronic liver disease while elucidating the polarization mechanism of macrophages under different microenvironments. Studies have demonstrated that inhibiting M1-type macrophage polarization or promoting M2-type polarization can effectively combat chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, and liver fibrosis. The PI3K/Akt pathway acts as a pivotal modulator of macrophage survival, migration, proliferation, and their responses to metabolism and inflammatory signals. Activating the PI3K/Akt pathway induces anti-inflammatory cytokine expression, resulting in the promotion of M2-like phenotype to facilitate tissue repair and resolution of inflammation. Conversely, inhibiting PI3K/Akt signaling could enhance the M1-like phenotype, which exacerbates liver damage. Targeting the PI3K/Akt pathway has tremendous potential as a therapeutic strategy for regulating macrophage polarization and activity to treat chronic liver diseases with plant chemicals, providing new avenues for liver disease treatment.