Natural Products Targeting Regulated Cell Death in Bladder Cancer: Pathway Mechanisms, Crosstalk and Intravesical Translation

The frequent recurrence and treatment resistance of bladder cancer have prompted interest in natural products that modulate regulated cell death (RCD). Although several compounds have shown activity in experimental models, their mechanisms of action and relevance to intravesical treatment remain unclear. This narrative review examines chemically defined natural compounds, metabolites, semisynthetic derivatives, and compositionally characterized extracts or preparations, and relates their effects on RCD to pathway crosstalk and intravesical delivery. We distinguish functional evidence of death pathway dependence from changes in associated markers and consider how resistance, treatment conditions, and cell type influence the response. Apoptosis is the most extensively studied pathway, involving mitochondrial priming, death receptor signaling, and suppression of survival networks. Ferroptosis has the strongest mechanistic support among non-apoptotic pathways, as evidenced by iron chelation, inhibition of lipid peroxidation, glutathione peroxidase 4 engagement, and perturbation of antioxidant defenses. Evidence for necroptosis, pyroptosis, and cuproptosis is limited; no direct evidence for disulfidptosis induced by a natural small molecule acting alone was identified in the reviewed bladder cancer literature. Emerging studies also report disulfidptosis-associated effects of selected formulations and anoikis-related responses, although these findings remain specific to the interventions studied. Autophagy can protect cells or contribute to cell death; however, impaired degradation can complicate the interpretation of autophagy markers. The balance between death pathways can shift with exposure and resistance states. Cell type also matters: inducing ferroptosis in tumor cells may support tumor control, whereas suppressing ferroptotic dysfunction in macrophages can preserve antitumor immunity. Translation remains limited by the separation between mechanism-focused studies and human intravesical trials, which have largely examined different agents. The former seldom assess tissue exposure or repeated-dose urothelial safety, whereas the latter report clinical activity and short-term tolerability without establishing dependence on a specific RCD pathway. Further development requires studies that link intravesical retention and tissue exposure to target engagement, and functionally test RCD while assessing antitumor efficacy and normal urothelial safety under repeated dosing.