Abstract: Liver fibrosis is a highly harmful chronic liver disease, with its core pathological link being the abnormal interaction between hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC). MEKK3, as a key upstream molecule in the MAPK pathway, may become a potential therapeutic target for liver fibrosis by regulating the biological functions and intercellular interactions of HSC and LSEC. Currently, Western medicine lacks specific drugs for anti-fibrosis, while traditional Chinese medicine (TCM) demonstrates unique therapeutic potential due to its multi-component and multi-target advantages, although the mechanism of action remains unclear. This article reviews the current research status of liver fibrosis, elucidates the core role of HSC-LSEC interaction in liver fibrosis and the synergistic influence of the liver microenvironment, and summarizes that active components of traditional Chinese medicine and classic compound prescriptions can exert anti-fibrotic effects by targeting and inhibiting MEKK3 to regulate this cell interaction network. In view of the limitations of existing research, future efforts are needed to deeply analyze the cell interaction mechanism mediated by MEKK3, carry out efficacy verification and clinical translation of traditional Chinese medicine, and provide theoretical support for the development of new anti-fibrotic traditional Chinese medicine drugs.