Figure 9.

Schematic summary of the potential crosstalk between hepatocytes, hepatic stellate cells and macrophages in the liver following Efavirenz (EFV) treatment. In hepatocytes, EFV induces endoplasmic reticulum (ER) stress and mitochondrial dysfunction characterized by an enhanced reactive oxygen species (ROS) production and mitochondrial mass, and a reduction in mitochondrial membrane potential (ΔΨ_m) and ATP levels, which leads to an accumulation of intracellular lipids [8,9,11]. These cellular events are associated with an increased nuclear translocation of NF-κB, which upregulates the expression of pro-inflammatory cytokines and the NLRP3 inflammasome. EFV also activates hepatic stellate cells, an effect associated with several EFV-induced actions such as enhanced oxidative stress and ER stress, and lipophagy. Moreover, EFV upregulates pro-inflammatory and fibrogenic mediators in these cells. Importantly, in both hepatocytes and hepatic stellate cells, EFV activates the NLRP3 inflammasome, which can lead to the release of damage-associated molecular patterns (DAMPs), amplifying the inflammatory response. Conversely, EFV produces macrophage polarization towards the anti-inflammatory/pro-resolving M2 phenotype, as shown by an increased expression of PPAR-γ and anti-inflammatory cytokines, which alleviates the pro-inflammatory and pro-fibrogenic response in hepatocytes and hepatic stellate cells.