Fig. 8.

Schematic diagram illustrating the function and mechanism of GPR65 in the progression of liver inflammation and fibrosis. Upon liver injury, increased or activated HMs-enriched GPR65 induces up-regulation of TNF-α and IL-6 via the Gαq-Ca²⁺-JNK/NF-κB pathways, while promoting the expression of TGF-β through the Gαq-Ca²⁺-MLK3-MKK7-JNK pathway in HMs, thus resulting in the damage of HCs and the activation of HSCs, and subsequently aggravate BDL- and CCl₄-induced liver inflammation, injury and fibrosis. In addition, pharmacological inhibition of GPR65 can block this process. BDL bile duct ligation, CCl₄ carbon tetrachloride, HC hepatocyte, HM hepatic macrophage, HSC hepatic stellate cell, MLK3 mixed lineage kinase 3, MKK7 mitogen-activated protein kinase kinase 7, NF-κB nuclear factor κB, JNK c-Jun N-terminal kinase, AP1 activator protein 1, TNF-α tumor necrosis factor-α, IL-6 interleukin-6, TGF-β transforming growth factor-β, DAMPs damage-associated molecular patterns