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Background: Arts and cultural engagement (ACEng) has been linked to physical and mental health across the life course, but the biological mechanisms underpinning these associations are not well understood. Proteomic profiling offers a way to explore biological pathways that may mediate these effects.

Objectives: To identify serum proteomic signatures associated with ACEng and examine their potential mediating role in long-term disease risk.

Methods: Data from approximately 6,000 adults (mean age = 53 years, SD = 18) in Understanding Society were analysed. Cross-sectional associations between ACEng and 184 neurological and cardiometabolic proteins were examined using multivariable linear regression, followed by functional enrichment analysis. Longitudinal mediation analyses assessed whether identified proteins mediated associations between ACEng and 14 cardiovascular, musculoskeletal, metabolic, neurological, and mental health conditions over a median follow-up of 20 years.

Results: Greater ACEng was associated with lower levels of 12 proteins and higher levels of six proteins after adjustment for sociodemographic confounders and correction for multiple testing. Enriched biological pathways included cell proliferation, receptor-mediated signaling, immune regulation, and inflammatory signaling. Mediation analyses showed that proteins partially explained associations between ACEng and disease risk—for example, MSR1 showed the largest mediation effects for stroke (11.81%), hypertension (11.27%), and diabetes (12.73%). Overall, proteins accounted for 15.95-36.92% of associations between ACEng and health outcomes.

Conclusion: This study provides the first evidence of distinct proteomic signatures associated with ACEng in a population-based sample. The findings enhance understanding of the biological mechanisms through which ACEng is linked to human health and disease.