A new perspective on AMD pathogenesis: a sequential Factor H-centered view of complement dysregulation.

Age-related macular degeneration (AMD) is a chronic, progressive, retinal disease that primarily affects older individuals and is one of the leading causes of blindness worldwide. Both genetic predisposition and environmental factors contribute to its development. Landmark genome-wide association studies (GWAS) positioned the complement system at the center of AMD research, opening new avenues for understanding disease mechanisms and developing targeted therapies. Among the key complement regulators, Factor H and its splice variant FHL-1, are best known for their roles in inhibiting the alternative pathway. Recent research has expanded our understanding of Factor H, revealing a range of non-canonical functions beyond complement regulation which might also affect AMD pathology. These new functions include roles in cell signaling, tissue protection, metabolism, homeostasis, and modulation of inflammation. In contrast, the related protein FHR1 which is also associated with AMD, exhibits pro-inflammatory properties, promoting monocyte recruitment and activation to facilitate clearance processes. In this review, we summarize the canonical and non-canonical functions of Factor H, FHL-1, and FHR1, and we show how the coordinated action of these three proteins integrates into the broader scope of AMD pathogenesis, including complement activation, inflammation, and photoreceptor degeneration. We also describe the current status of approved complement inhibitors in AMD and emerging therapeutic targets within the complement cascade.