Gut Parabacteroides distasonis‐derived Indole‐3‐Acetic Acid Promotes Phospholipid Remodeling and Enhances Ferroptosis Sensitivity via the AhR‐FASN Axis in Bladder Cancer

Abstract The development of bladder cancer is a complex, multistep process influenced by both genetic and environmental factors, but its exact etiology remains unclear. Increasing evidence suggests that gut microbiota dysregulation can impact the initiation and progression of cancers, including colorectal cancer, breast cancer, and pancreatic cancer. This study observes that the beneficial gut bacterium Parabacteroides distasonis ( P. distasonis ) is significantly decreased in bladder cancer patients, and its low abundance is strongly associated with poor prognosis. P. distasonis is a next‐generation probiotic which plays a vital role in human health. Furthermore, this work finds that P. distasonis culture medium inhibits metastasis and proliferation of bladder cancer cells in vitro and in vivo. This work identifies that indole‐3‐acetic acid (3‐IAA) produced by P. distasonis exerting similar tumor‐suppressive effects. Mechanistically, 3‐IAA activates the aryl hydrocarbon receptor (AhR), which in turn downregulates fatty acid synthase (FASN) transcription in bladder cancer cells. Notably, the reduction of FASN expression decreases the ratio of MUFAs to PUFAs, thereby increasing ferroptosis sensitivity in bladder cancer cells. Collectively, this study demonstrates that P. distasonis ‐derived 3‐IAA can inhibit bladder cancer metastasis and proliferation, highlighting the AhR‐FASN axis as a promising therapeutic target to inhibit bladder cancer progression.