Macular fibrosis secondary to neovascular age-related macular degeneration: from clinic to biology

Macular subretinal fibrosis represents the end-stage complication of neovascular age-related macular degeneration (nAMD). Despite the widespread use of anti-VEGF therapy, between 20 and 67% of nAMD patients develop this sight-threatening condition within 2 to 7 years, making fibrosis one of the main reasons responsible for anti-VEGF resistance and irreversible visual loss. Unlike the quiescent scar of a healed skin wound, subretinal fibrosis is a dynamic, vascularised lesion characterised by persistent and active inflammation, a process aptly termed "hot fibrosis". The molecular mechanisms that drive the conversion of neovascularisation into fibrovascular membrane remain poorly defined. This review summarises the clinical features of macular fibrosis in nAMD. It will then detail the pathological insights gained from advanced clinical high-resolution imaging and post-mortem histopathological investigations. We will also explore how advances in our understanding of the pathogenesis of macular fibrosis, as revealed by preclinical models, are uncovering novel therapeutic targets. Promising approaches include dual-targeting agents (e.g., inhibiting VEGF and Ang-2 or complement pathways), as well as repurposing FDA-approved anti-fibrotics, such as pirfenidone or nintedanib, for ocular delivery. The repurposing of drugs with established safety profiles, reformulated for local intraocular use, offers a particularly resource-efficient pathway.