A Mechanistic Dissection of Multifaceted Complement Attack in Age‐Related Macular Degeneration Reveals the Superiority of C3 Inhibition

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in the elderly, and geographic atrophy (GA) represents its advanced atrophic form. While C5 and C3 inhibitors have shown efficacy in slowing GA progression, the precise pathogenic roles of individual complement effectors and the optimal inhibition strategy remain subjects of ongoing debate. This study employs an in vitro model using A2E-laden retinal pigment epithelium (RPE) cells and normal human serum to systematically investigate complement-mediated RPE degeneration and compare the protective effects of different complement-targeting strategies. We demonstrate that C5 blockade, while preventing lytic cell death caused by the membrane attack complex (MAC), fails to fully restore mitochondrial function or prevent phagolysosomal damage. Crucially, these C5-independent pathologies involve C3 activation products. In contrast, upstream C3 inhibition comprehensively protects RPE cells by ameliorating these diverse pathological processes. Our findings provide a detailed mechanistic understanding of complement-driven RPE degeneration and support a mechanistic rationale for an upstream C3-targeting strategy in GA secondary to AMD.