Deciphering the Impact of High-Fat Diet and Tobacco Exposure on Urothelial Integrity and Bladder Inflammation: A Mechanistic Systematic Review

Lower urinary tract symptoms (LUTS) are a major global health burden and are closely linked to urothelial dysfunction and chronic inflammation. Modifiable lifestyle factors, especially exposure to high-fat diets (HFDs) and tobacco products, appear to contribute to bladder pathology through overlapping biological pathways, but how they interact mechanistically is still not well understood. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-guided systematic review synthesized mechanistic and epidemiological evidence on how HFD and tobacco products affect urothelial integrity, bladder inflammation, and the development or progression of LUTS. PubMed/MEDLINE, Cochrane Library, Scopus, Web of Science, and Google Scholar were searched for 2012-2025 studies; 14 human studies and 18 animal model studies met eligibility, and findings were qualitatively summarized with risk-of-bias assessment using appropriate tools. Evidence consistently shows independent harms from both exposures, with HFD driving metabolic inflammation, oxidative stress, and hypoxia, causing urothelial barrier disruption, detrusor fibrosis, altered contractility, and increased cystitis susceptibility. Tobacco, including tobacco-specific nitrosamines (TSNAs) and nicotine, causes urothelial injury, DNA damage, chronic inflammation, and epithelial hyperplasia, aligning with worse LUTS and higher bladder cancer risk. Both act via shared mechanisms such as oxidative stress, nuclear factor kappa B (NF-κB) activation, and endothelial dysfunction, supporting the critical role of lifestyle interventions for bladder health.