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CXCR4 plays a pivotal role in liver fibrosis (LF) by mediating the activation of hepatic stellate cells (HSCs), which contribute to extracellular matrix (ECM) deposition and scar formation. The CXCR4/CXCL12 axis is essential in fibrogenesis, promoting HSCs activation, inflammation, and angiogenesis, which exacerbates fibrosis and creates an environment conducive to hepatocellular carcinoma (HCC) development. In HCC, CXCR4 signaling supports tumor cell proliferation, survival, and metastasis, linking chronic liver injury to cancer progression. Recent advancements in targeted drug delivery have facilitated the development of CXCR4-targeted therapies, improving treatment efficacy while minimizing systemic toxicity. This review examines the interactions between CXCR4 and its ligand CXCL12, the associated signaling pathways, and their role in LF and HCC. Furthermore, it explores CXCR4 as a therapeutic target, focusing on CXCR4 blockers, peptide inhibitors, and gene silencing/editing strategies. The review also highlights various CXCR4-targeted nano therapeutic strategies, such as liposomes, lipid NPs, microbubbles, polymeric NPs incorporating siRNA, miRNA, small molecules, peptides etc for the management of LF and HCC. Additionally, the review addresses the clinical progress of monoclonal antibodies, small molecules, and peptides targeting CXCR4 in both preclinical and clinical trials. Challenges and future directions of CXCR4-targeted nanotherapeutic are also discussed. In conclusion, this review emphasizes the therapeutic potential of CXCR4-targeted nanotherapeutic strategies for combating LF and HCC.