Sema3C promotes hepatocellular carcinoma (HCC) progression by reshaping the tumor stromal microenvironment. Sema3C is significantly upregulated in fibrotic liver, HCC tissues, peripheral blood of HCC patients, and sorafenib-resistant tissues and cells. Its overexpression correlates with stemness properties in HCC. Sema3C interacts with NRP1 and ITGB1, activating downstream AKT/Gli1/c-Myc signaling pathways to enhance HCC self-renewal and tumor initiation. Sema3C also promotes extracellular matrix (ECM) contraction and collagen deposition in vivo, while promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacts with NRP1 and ITGB1 in HSCs, activating NF-κB signaling, which stimulates IL-6 production and upregulates HMGCR expression, enhancing cholesterol synthesis in HSCs. CAF-secreted TGF-β1 activates AP1 signaling, augmenting Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. Sema3C serves as a novel biomarker facilitating crosstalk between cancer stem cells (CSCs) and the stroma during hepatocarcinogenesis, offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC. Sema3C promotes stemness maintenance and initiation in HCC by activating the AKT/Gli1/c-Myc signaling axis. Sema3C maintains HCC stemness via NRP1 and ITGB1, which are critical receptors for Sema3C. Sema3C promotes ECM remodeling and HSC activation, contributing to the supportive niche in the tumor microenvironment. Sema3C induces HSC activation by upregulating IL6 secretion and cholesterol synthesis through NRP1 and ITGB1. CAFs-derived TGF-β1 upregulates Sema3C expression via AP1 in HCC cells, establishing a vicious cycle that accelerates HCC progression. Inhibition of Sema3C enhances sorafenib efficacy in HCC mouse models. Sema3C plays a key role in mediating bidirectional communication between CSCs and the tumor stroma, driving a vicious cycle that accelerates HCC progression.Sema3C promotes hepatocellular carcinoma (HCC) progression by reshaping the tumor stromal microenvironment. Sema3C is significantly upregulated in fibrotic liver, HCC tissues, peripheral blood of HCC patients, and sorafenib-resistant tissues and cells. Its overexpression correlates with stemness properties in HCC. Sema3C interacts with NRP1 and ITGB1, activating downstream AKT/Gli1/c-Myc signaling pathways to enhance HCC self-renewal and tumor initiation. Sema3C also promotes extracellular matrix (ECM) contraction and collagen deposition in vivo, while promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacts with NRP1 and ITGB1 in HSCs, activating NF-κB signaling, which stimulates IL-6 production and upregulates HMGCR expression, enhancing cholesterol synthesis in HSCs. CAF-secreted TGF-β1 activates AP1 signaling, augmenting Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. Sema3C serves as a novel biomarker facilitating crosstalk between cancer stem cells (CSCs) and the stroma during hepatocarcinogenesis, offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC. Sema3C promotes stemness maintenance and initiation in HCC by activating the AKT/Gli1/c-Myc signaling axis. Sema3C maintains HCC stemness via NRP1 and ITGB1, which are critical receptors for Sema3C. Sema3C promotes ECM remodeling and HSC activation, contributing to the supportive niche in the tumor microenvironment. Sema3C induces HSC activation by upregulating IL6 secretion and cholesterol synthesis through NRP1 and ITGB1. CAFs-derived TGF-β1 upregulates Sema3C expression via AP1 in HCC cells, establishing a vicious cycle that accelerates HCC progression. Inhibition of Sema3C enhances sorafenib efficacy in HCC mouse models. Sema3C plays a key role in mediating bidirectional communication between CSCs and the tumor stroma, driving a vicious cycle that accelerates HCC progression.