Complement C3 is associated with cancer-induced frailty: genetic and clinical evidence.

Background: Frailty is a degenerative geriatric syndrome characterized by declining muscle mass and function, unintentional weight loss, and fatigue. It is a key risk factor for many geriatric diseases and poor postoperative outcomes. Currently, pathogenesis remains unclear, and apart from nutritional support and exercise, no pharmacological interventions are available. Notably, the frailty phenotype is also a major feature in patients with advanced-stage cancer, and both frailty and advanced cancer are characterized by dysregulation of nutritional and energy metabolism. Consequently, cancer serves as a novel accelerated model for investigating the mechanisms underlying frailty development. Methods: The phenome-wide association study (PheWAS) framework was employed to systematically analyze the causal relationship between 264 cancer types and frailty, and to identify candidate cancer types directly causally associated with frailty. 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. Results: 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 ( Conclusion: 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.