Table 1_Complement C3 is associated with cancer-induced frailty: genetic and clinical evidence.xlsx

A large-scale analysis was conducted to assess the causal relationship between “candidate cancer- Icelandic peripheral blood proteome-frailty” and to further explore the characteristics and patterns of the key proteins mediating cancer-induced frailty using the two-sample Mendelian randomization method. Finally, the correlation between key candidate proteins and frailty was verified using peripheral blood from a 100-case colorectal cancer (CRC) cohort.</p>Results<p>The PheWAS analysis identified 21 cancer types with significant causal associations with frailty among the 264 cancers examined.

An in-depth analysis of the top 5 cancer types revealed that the mechanisms by which they induce frailty exhibit both prominent shared features and distinct characteristics. Shared signaling pathways included stress responses, immune processes, and metabolic pathways. Among these, immune-related pathways involving complement component C3 (C3), lipocalin-2 (LCN2), and coagulation factor V (F5) emerged as key shared mechanisms across multiple cancer types.

Finally, validation in an independent clinical cohort of patients with CRC (n = 100) demonstrated that circulating C3 levels were positively correlated with frailty severity and the frailty-related comorbidity index, and negatively correlated with serum albumin levels.</p>Conclusion<p>This study systematically elucidated the causal relationships between cancer and frailty, identified multiple candidate proteins that may drive frailty progression, and demonstrated that complement C3 is associated with frailty development.

Furthermore, we propose that cancer serves as a novel accelerated model for investigating the mechanisms underlying frailty. These findings provide new insights into the biological mechanisms underlying frailty and identify a series of promising molecular targets for future mechanistic studies and therapeutic interventions.</p>