Aims <p>Recent clinical studies have revealed a significant correlation between Akkermansia muciniphila (Akk) and colorectal cancer (CRC). To elucidate the fundamental mechanisms by which Akk inhibits the proliferation of CRC, this study applied pasteurized Akk, Akk metabolites, and their postbiotics on Caco-2 cells. </p> Methods <p>Cell proliferation, lactate dehydrogenase (LDH) release, and reactive oxygen species (ROS) levels were employed as screening indicators. Based on single-cell transcriptomics analysis, we investigated the mechanisms through which Akk inhibits the proliferation of Caco-2 cells. Finally, verification was conducted using three characteristic indicators: malondialdehyde (MDA), glutathione (GSH), and Fe2+, ferroptosis inhibitor (Fer-1) served as a control. Cell scratch assays and flow cytometry experiments are used to verify cell death.</p> Results <p>The findings indicate that metabolites of Akk exert the most potent inhibitory effect on Caco-2 cells. Notably, there was a significant increase in LDH and ROS levels, while metabolic pathways associated with ferroptosis were markedly enriched. Furthermore, there was an increase in Fe2+ and MDA content accompanied by a decrease in GSH levels. Cell proliferation ability declined sharply, and a large number of cells die. </p> Conclusions <p>This study confirms that metabolites of Akk can indeed suppress CRC cell proliferation through the ferroptosis pathway.</p>