Allostatic load (AL), reflecting chronic physiological stress across neuroendocrine, immune, and metabolic systems, may contribute to the onset and prognosis of multiple cancers via inflammation and stress-related injury. However, the associations between AL and kidney cancer (KC) remain unclear. And large-scale evidence linking AL to KC risk, prognosis, and molecular mechanisms is lacking.In this Prospective UK Biobank cohort study, 334,754 Participants were analyzed for KC incidence, 357 KC Patients for mortality, and 36,120 participants for proteomic mediation. Proteomic mediation was performed using Med4way analysis; protein trajectories were analyzed using locally weighted regression smoothing (LOESS) regression. The expression profiles of key mediator genes were validated by single-cell RNA sequencing. Enrichment analyses were conducted to characterize mediator proteins by biological pathways, tissue specificity, and cell-type distribution. An AL-mediated proteins-based prediction model was developed via LASSO-Cox regression.During mean follow-up of 13.2 years, participants in the highest AL quintile had increased KC incidence (HR 1.70, 95% CI 1.38-2.10). Among KC patients, high AL was associated with increased mortality (HR 3.10, 95% CI 1.51-6.36). Proteins mediating AL-KC associations included HAVCR1, GDF15, TNFRSF11A, FSTL3, and CD83; HAVCR1 showed strongest mediation (72.69%) and distinct pre-diagnostic trajectory. Functional enrichment revealed these proteins were jointly involved in immune regulation, stress response, and epithelial signaling pathways. The predictive model incorporating NOS3, SULT2A1, HAVCR1, FSTL3, and sex achieved robust performance (10-year AUC 0.80) for KC Prediction.AL is associated with increased KC incidence and mortality, mediated through inflammatory and metabolic proteins. These findings underscore chronic physiological stress as a significant factor in KC pathogenesis, providing potential biomarkers for early risk assessment and targeted prevention.© 2025. The Author(s).