Postoperative exosomal miR-1246 fuels hepatocellular carcinoma metastasis via BMP9-SMAD7 axis suppression

Emerging evidence highlights the perioperative period, particularly the immediate postoperative window of days to weeks, as a critical phase influencing long-term cancer outcomes. Here, we found that hepatocellular carcinoma (HCC) cells cultured with postoperative serum exhibited enhanced anoikis resistance, invasion, migration, and increased potential for lung metastasis compared to those cultured with preoperative serum. This pro-metastatic effect was attributed to serum-derived exosomes. We therefore performed high-throughput miRNA sequencing to profile miRNAs in exosomes derived from the preoperative and postoperative serum of HCC patients. Sequencing analysis revealed a significant upregulation of exosomal miR-1246 in the majority of postoperative HCC patients. Mechanistically, exosomal miR-1246 directly targeted BMP9 mRNA, suppressing its protein expression. This led to inactivation of the downstream metastasis-inhibitory pathway mediated by SMAD7, ultimately accelerating HCC metastasis. Functional rescue experiments confirmed that either inhibiting miR-1246 or exogenously restoring BMP9 effectively reversed this pro-metastatic phenotype both in vitro and in vivo. In conclusion, our study elucidates a molecular mechanism by which postoperative exosomal miR-1246 promotes HCC metastasis via targeting the BMP9-SMAD7 signaling axis, thereby identifying a potential therapeutic target for inhibiting postoperative metastatic risk.