Abstract
<title>Abstract</title> <p> <bold>Background</bold> The hepatic accumulation of senescent macrophages is a pivotal driver in the pathogenesis of MAFLD. However, the mechanisms underlying their persistence and the strategies for their elimination remain poorly understood. Our investigation revealed that these macrophages exhibit significant resistance to ferroptosis. Notably, pentadecanoic acid (C15:0), a metabolite derived from <italic>Bacteroides acidifaciens</italic> , specifically targets this ferroptosis resistance, thereby presenting a promising therapeutic modality for MAFLD. <bold>Methods</bold> Whole-genome sequencing confirmed the ability of <italic>B.acidifaciens</italic> to synthesize C15:0. We subsequently quantified bacterial loads and metabolite concentrations in clinical specimens. These findings were integrated with interventional experiments in murine MAFLD models, utilizing macrophage-specific Jun knockdown systems and oral administration of <italic>B.acidifaciens</italic> . To elucidate the mechanisms governing the clearance of senescent macrophages, we employed single-cell RNA sequencing, ChIP-qPCR, and complementary methodologies. <bold>Results</bold> Our data indicate that senescent macrophages exhibit reduced expression of phosphorylated c-Jun and GPX4, along with impaired NCOA4-mediated ferritinophagy, a defect that confers resistance to ferroptosis. In contrast, C15:0 derived from <italic>B.acidifaciens</italic> activates the JNK signaling cascade, enhancing Jun phosphorylation and subsequently upregulating NCOA4. This mechanistic pathway effectively reinstates ferroptosis sensitivity in senescent macrophages, thereby curbing their pathological accumulation and ameliorating hepatic steatosis and inflammation in vivo. Notably, these therapeutic effects were completely abolished in mice lacking macrophage-specific Jun, definitively establishing the JNK-Jun-NCOA4 axis as the critical mediator of this microbiota-targeted intervention. <bold>Conclusions</bold> Our results elucidate a microbiota-modulated gut-liver axis in which C15:0 targets the JNK-Jun-NCOA4 signaling pathway to overcome ferroptosis resistance in senescent macrophages. This study positions both <italic>B.acidifaciens</italic> and its metabolite pentadecanoic acid as potential novel therapeutic agents for the treatment of MAFLD. </p>