<p>Liver fibrosis is a chronic disease caused by various etiologies, including dysregulated interactions among hepatocytes, KCs, and HSCs. Studies have shown that the S100 protein family plays an important role in liver fibrosis, especially the S100A4/A6/A10/A11 proteins; however, the effects of hepatocyte-derived S100A4/A6/A10/A11 proteins on the crosstalk between KCs and HSCs in liver fibrosis are unknown. The aim of this study was to investigate how hepatocyte-derived S100A4/A6/A10/A11 proteins modulate KC and HSC activation during liver fibrosis.&#xa0;Fibrotic, HCC and ICC human liver paraffin-embedded block samples were obtained. A CCl₄-induced liver fibrosis model was established, and in this model, S100A4/A6/A10/A11 proteins were blocked using specific antibodies. AML-12 mouse hepatocytes, KCs, and HSCs were used in vitro. During liver fibrosis, S100A4/A6/A10/A11 proteins are released by hepatocytes and function as DAMPs that activate KCs via the p38 and JNK signaling pathways. This activation triggers the release of inflammatory cytokines, which in turn promote HSC activation and collagen deposition through a TGF-β/SMAD2-dependent mechanism. Moreover, S100A4/A6/A10/A11 proteins can directly stimulate HSC activation and collagen deposition via the TGF-β/SMAD2 pathway. Blocking S100A4/A6/A10/A11 proteins significantly attenuated the release of inflammatory cytokines and reduced collagen deposition. Clinical evidence further indicates that the expression of S100A4/A6/A10/A11 proteins is significantly upregulated in liver tissues from patients with HCC and ICC.&#xa0;This study reveals a dual regulatory mechanism in liver fibrosis: S100A4/A6/A10/A11 proteins derived from hepatocytes not only indirectly promote HSC activation by stimulating KCs to release pro-inflammatory factors but also directly activate HSCs. These findings highlight the potential of this group of S100 proteins as a promising therapeutic target for liver fibrosis.</p>