Decoding Age-Related Macular Degeneration: From Molecular Pathways to Cutting-edge Therapies

Abstract

Age-related macular degeneration (AMD) represents a leading cause of irreversible vision loss worldwide, characterized by the progressive degeneration of the macular region of the retina, involving photoreceptor death and dysfunction of retinal pigment epithelial cells. AMD is a complex multifactorial disorder driven by a convergence of genetic, epigenetic, inflammatory, and environmental mechanisms. This review explores the multifaceted molecular underpinnings of AMD, with particular emphasis on the dynamic crosstalk between genetic risk factors, DNA methylation, non-coding RNAs, oxidative stress, mitochondrial dysfunction, chronic inflammation, and complement system dysregulation. We also highlight the pathogenic roles of microglial activation, endoplasmic reticulum stress, impaired autophagy, and the significant contributions of vascular endothelial growth factor (VEGF) signaling and extracellular matrix disruptions in drusen formation. Current therapeutic strategies focus on anti-VEGF therapies, complement pathway inhibitors, gene-based interventions, epigenetic modulators, and stem cell transplantation, all of which have shown promise in clinical trials. However, challenges such as disease heterogeneity, treatment resistance, limitations in preclinical models, and variable patient responses continue to hinder optimal therapeutic outcomes. Future research must integrate single-cell multi-omics, retinal organoid models, and artificial intelligence to better understand the cellular heterogeneity and mechanistic interplay of disease processes. This will be crucial for advancing precision medicine and developing multi-target combinatorial interventions. The objective of this review is to summarize recent advances in the molecular mechanisms of AMD and to highlight emerging therapeutic strategies that may guide future research and clinical translation.