Natural Products Targeting Acetylation in Bladder Cancer: Mechanistic Basis, Therapeutic Potential, and Future Perspectives

Bladder cancer remains a major clinical challenge because of its high recurrence rate, marked molecular heterogeneity, frequent progression, and limited durability of current therapeutic strategies. Increasing evidence indicates that acetylation, as a reversible and druggable epigenetic modification, plays a central role in bladder cancer biology by linking chromatin remodeling to transcriptional regulation, DNA damage repair, metabolic adaptation, and immune modulation. Both histone and non-histone acetylation are frequently dysregulated in bladder cancer, and these alterations contribute to multiple malignant phenotypes, including sustained proliferation, defective cell-cycle control, apoptosis evasion, epithelial–mesenchymal transition, metastatic progression, and therapeutic resistance. In this review, we summarize the mechanistic basis of acetylation imbalance in bladder cancer, with particular emphasis on the roles of histone acetyltransferases, histone deacetylases, sirtuins, and acetylation-associated metabolic regulators. We further discuss the emerging evidence that natural products can modulate acetylation-related pathways in bladder cancer, mainly through targeting HDAC-dependent histone deacetylation and SIRT1-associated non-histone deacetylation. Representative compounds, including sulforaphane, erucin, puerarin, capsaicin, curcumin, trichostatin A, trichostatin C, and pinocembrin, highlight the potential of natural products to suppress tumor growth, promote apoptosis, impair migration, and enhance antitumor immunity through acetylation-related mechanisms. Beyond summarizing individual agents, the evidence was evaluated based on the integration of acetylation-related target engagement, acetylation remodeling, and bladder cancer-relevant phenotypic outcomes. The current evidence is heterogeneous. SFN/ECN, capsaicin, and pinocembrin offer the most convincing bladder cancer-specific support, whereas several other compounds remain limited by context-dependent effects, indirect pathway inference, or incomplete validation of the proposed acetylation mechanisms. These findings support an evidence-oriented translational framework that prioritizes natural products according to mechanistic robustness, bladder cancer specificity, and combination potential. Overall, acetylation-targeting natural products represent a promising but still evolving therapeutic strategy for bladder cancer, warranting further subtype-specific, mechanistically rigorous, and translationally oriented investigation.