<p>Shugan Jianpi Formula (SGJPF), a traditional Chinese herbal formulation, has been clinically used for decades in the management of various chronic liver diseases, including liver fibrosis (LF). Previous studies have demonstrated the efficacy of SGJPF in ameliorating pathological manifestations in murine models of LF. However, the precise molecular mechanisms underlying its therapeutic effects remains unclear. In the present study, we aimed to explore the therapeutic mechanisms of SGJPF through comprehensive analysis of LncRNA-mRNA co-expression network.The therapeutic efficacy of SGJPF in a CCL₄-induced LF murine model was assessed by histopathological alterations, α-smooth muscle actin (α-SMA) and collagen Ⅰ expression. To elucidate the molecular mechanisms underlying the efficacy of SGJPF, whole transcriptome RNA sequencing technology was conducted to identify the LncRNAs and mRNAs expression profiles across control, model, and SGJPF-treated groups. GO function and KEGG pathway enrichment analysis was performed to identify the biological functions and signaling pathways associated with the differentially expressed genes (DEGs). Subsequently, the hub LncRNAs and mRNAs were identified based on fold change and correlation analysis. Finally, biological relevance of these core genes were further validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in mouse liver tissue, revealing the regulatory interactions between LncRNAs and their target mRNAs. Compared with the control group, 401 differentially expressed (DE) LncRNAs and 1224 DE mRNAs were found in the model group. In addition, compared with the model group, 98 DE LncRNAs and 147 DE mRNAs were identified following treatment with SGJPF. Subsequently, 31 DE LncRNAs and 39 DE mRNAs were obtained and served as potential target genes of SGJPF. Functional annotation of the 31 DE LncRNAs revealed predominant involvement in small molecule metabolic processes, with significant associations observed in circadian rhythm regulation, p53 signaling pathway, TGF beta signaling pathway, and Hippo signaling pathway. Correlation analysis indicated significant associations between these 31 DE LncRNAs and 39 DE mRNAs (|PCC|&gt; 0.65, P &lt; 0.05). Additionally, the expression of 2 LncRNAs (Gm28857, D030074P21Rik) and 5 mRNAs (Cdkn1a, Id1, Id4, Wnt9b, Gadd45g) were confirmed by RT-qPCR in mouse liver tissue, which were consistent with RNA sequencing data. This study delineates the comprehensive LncRNA/mRNA expression profiles in LF treated with SGJPF, which may provide valuable insights into the molecular mechanisms underlying LF pathogenesis and identifying potential therapeutic targets for further investigation.</p> Graphical Abstract <p></p>