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  • EMERGING MOLECULAR TARGETS AND MECHANISMS OF DRUG RESISTANCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: TOWARD PERSONALIZED OPHTHALMIC THERAPY

  • Delnia Khadiry,1,* Zahra nasrollahi ,2
    1. Kermanshah University of Medical Science
    2. Kermanshah University of Medical Science


  • Introduction: Neovascular diseases of the retina and choroid, such as neovascular age-related macular degeneration (nAMD) and diabetic retinopathy, are leading causes of visual impairment. Vascular endothelial growth factor (VEGF) is considered one of the most critical drivers of neovascularization. While anti-VEGF therapies have significantly improved patient outcomes, challenges such as disease recurrence, incomplete responses, and diminished efficacy in certain patients persist. Emerging evidence suggests that following VEGF inhibition, metabolic adjustments, alternative angiogenic pathways, hypoxia, inflammation, oxidative stress, and vascular instability may play roles in sustaining neovascularization. Exploring these molecular targets can pave the way for targeted and combination therapies. This narrative review focuses on the mechanisms underlying incomplete response or resistance to anti-VEGF therapy.
  • Methods: A narrative review was conducted using PubMed as the sole database for the period between 2015 and 2026. The search focused on articles related to ocular neovascularization, anti-VEGF resistance, alternative molecular pathways, and emerging therapeutic targets. Original human, animal, and in vitro studies were included. Studies were excluded if they did not investigate underlying molecular targets or resistance mechanisms (e.g., studies focusing solely on switching or dosing strategies for currently available anti-VEGF agents), or if they were systematic reviews and meta-analyses. Some secondary studies were also excluded to maintain a focused narrative review aimed at constructing a clear mechanistic-therapeutic framework. Studies were selected and analyzed based on their direct relevance to three primary research axes: 1) anti-VEGF resistance, 2) identification of alternative molecular pathways, and 3) investigation of novel therapeutic targets. Data were synthesized to link resistance mechanisms to newly identified targets. Ultimately, 10 articles were utilized for the synthesis of evidence.
  • Results: The selected studies demonstrated that resistance to anti-VEGF is a multifactorial phenomenon and is not limited to a resurgence of VEGF levels. Beyond VEGF-dependent signaling, several distinct axes have been identified. Targeting ferrochelatase (FECH) inhibited the migration, proliferation, and tube formation of endothelial cells by modulating the eNOS/HIF-1α/VEGFR2 axis. Activation of the Angiopoietin-Tie2 pathway also showed inhibition of CNV, reduction of hypoxia and vascular leakage, and choriocapillary remodeling, presenting it as a complementary approach to VEGF inhibition. Novel pathways, including Tie2/Angiopoietin, HIF-2α/PAI-1, LRG1/TGF-β, Scg3, p53, and CXCR4, were associated with changes in angiogenic effects in animal models. Specifically, the CD148-activating peptide provides a distinct mechanism to disrupt endothelial microcapillary formation. Resistance is significantly linked to immune cell infiltration (B memory, plasma, and CD8+ cells) and reduced oxidative stress resistance. Additionally, SOD1 gene expression may mitigate immune-driven resistance. These findings support a shift toward combination therapies, where Tie2 may modulate the consequences of chronic VEGF inhibition by maintaining vascular integrity and reducing hypoxia.
  • Conclusion: Anti-VEGF resistance in nAMD is driven by a complex network of metabolic, immune, and alternative signaling pathways. Emerging targets such as FECH, CD148, p53, LRG1, CXCR4, SOD1, and Tie2 provide a roadmap for developing personalized, multi-targeted combination therapies to improve long-term visual outcomes in nAMD patients. Integrated approaches that target VEGF alongside complementary pathways may serve as a strategy to overcome incomplete responses. Future research should focus on identifying biomarkers capable of predicting treatment response and resistance, as well as evaluating combination therapies that target complementary mechanisms.
  • Keywords: Anti-VEGF Resistance, Neovascular AMD, Therapeutic Targets

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