Biochanin A Activates Mitochondrial UPR to Protect the Host against Pathogenic Bacterial Infection through the Conserved Transcription Factor ATFS-1/ATF5

Abstract

Biochanin A (BCA) is a natural isoflavone found in chickpeas and soybeans. Although its biological activity is well established, the role of BCA in anti-infective immunity has not yet been fully elucidated. In this study, we demonstrated that BCA exploited the transcription factor ATFS-1 to trigger the mitochondrial unfolded protein response (UPRmt). In Caenorhabditis elegans (C. elegans), BCA increased resistance to Pseudomonas aeruginosa (P. aeruginosa PA14) and other pathogens in a dosage-dependent manner by reducing the intestinal bacterial load rather than directly inhibiting bacterial proliferation. By screening classical signaling pathways, we found that the BCA-mediated protective effect was entirely dependent on the atfs-1 gene, as BCA induced the nuclear translocation of ATFS-1 and upregulated UPRmt and immune effector factors. Notably, this mechanism was evolutionarily conserved. In a mouse model, BCA dose-dependently increased survival rates, reduced bacterial load in the lungs, and upregulated the expression of ATF5 (the mammalian homolog of ATFS-1) and mitochondrial chaperone proteins. This study is the first to reveal a cross-species conserved link between BCA, the mitochondrial stress response, and the host immune system, providing a promising therapeutic target for the management of clinical bacterial infections.