Bridging Mechanism and Therapy in Ocular Disease: Mitochondrial, Vascular, and Immune Pathways in the Eye

There is an increasing global burden of ocular disorders, with an estimated 43.3 million people worldwide currently blind and a further 295 million living with moderate-to-severe vision impairment, driven by a complex pathogenesis that involves multiple cascade failures ranging from mitochondrial dysfunction to chronic neuroinflammation and blood–retinal barrier breakdown. This narrative review synthesizes peer-reviewed literature identified through targeted searches of PubMed/MEDLINE, Embase, and the Cochrane Library, prioritizing publications from the last five years and supplemented by foundational studies where necessary, to examine molecular mechanisms underlying both anterior and posterior segment pathologies, including Fuchs endothelial corneal dystrophy (FECD), diabetic macular edema (DME), age-related macular degeneration (AMD), and antibody-mediated optic neuritis. We link the most recent clinical insights into the structural abnormalities of these disorders with translational research advances, examining how genetic drivers such as the TCF4 trinucleotide repeat expansion, vascular endothelial growth factor (VEGF) signaling, complement system dysregulation, and antibody-specific neuroinflammatory injury converge on shared cellular vulnerabilities across otherwise distinct ocular tissues, while explicitly noting where this convergence is well evidenced and where it remains hypothesis-generating. We also evaluate how novel imaging methods, including optical coherence tomography (OCT) and OCT angiography (OCTA), together with emerging artificial intelligence (AI)-assisted diagnostic tools, are reshaping early disease detection. Within these four index conditions, we examine therapeutic classes across a spectrum of evidentiary maturity, from complement inhibitors and anti-VEGF agents already altering clinical management of AMD and DME, to gene therapy and mitochondrial-stabilizing strategies that remain at the preclinical or early-investigational stage; adjacent pharmacological strategies whose supporting evidence was generated outside these four conditions are addressed separately in an appendix rather than treated as part of the core evidence base. To make the degree of mechanistic convergence explicit rather than assumed, we constructed a four-domain evidentiary matrix grading mitochondrial, microvascular/barrier, complement/innate immune, and neuroinflammatory evidence for each condition; no single condition showed strong evidence across all four domains, and the four conditions differed meaningfully in which domains dominated their pathogenesis. As a narrative rather than systematic review with a non-systematic search strategy and single-reviewer evidence grading, this synthesis should be read with those limitations in mind. Decoding complex networks of cellular and systemic processes in ocular disease remains critical to developing high-efficiency therapeutics that could potentially preserve ocular cellular homeostasis and halt progressive visual decline.