Objective <p>The aim of this study was to investigate the association of microRNA-345-3p (miR-345-3p) with liver metastasis in colorectal cancer (CRC) and to explore its underlying molecular mechanisms using in vitro approaches.</p> Methods <p>Serum specimens were collected from 110 CRC patients and 90 healthy individuals. Quantitative real-time PCR (qRT-PCR) was employed to assess the expression levels of miR-345-3p and KH RNA binding domain containing, signal transduction associated 1 (KHDRBS1) expression. The associations of miR-345-3p with clinical pathological characteristics, survival, and liver metastasis were analyzed. In vitro cell experiments were conducted to validate the effects of miR-345-3p on CRC cell growth and epithelial-mesenchymal transition (EMT). Target genes and signaling pathways were verified using luciferase reporter assays, rescue experiments, and Western blot analysis.</p> Results <p>A significant decrease in miR-345-3p expression was observed in CRC patients with liver metastasis. Low levels of miR-345-3p were correlated with advanced tumor node metastasis (TNM) stages, deeper invasion, lymph node metastasis, and poorer prognosis. Overexpression of miR-345-3p inhibited CRC cell growth and suppressed EMT-associated molecular changes. Bioinformatics analyses and experimental results confirmed KHDRBS1 as a direct target gene of miR-345-3p. Furthermore, rescue experiments demonstrated that overexpression of KHDRBS1 reverses the tumor-suppressive effects of miR-345-3p, indicating that miR-345-3p functions by regulating the transforming growth factor-β (TGF-β) signaling pathway.</p> Conclusions <p>Decreased circulating levels of miR-345-3p are associated with liver metastasis in CRC. In vitro studies suggest that miR-345-3p may exert its tumor-suppressive effects by targeting KHDRBS1 and suppressing the TGF-β signaling pathway, thereby inhibiting CRC cell migration and invasive capacity.</p>