bims-mideyd 2026-11-01 papers

Antioxidants (Basel). 2026 Oct 19. pii: 1351. [Epub ahead of print]15(10):

The Environmental Exposome and Age-Related Macular Degeneration: Oxidative Stress as a Molecular Link.

Age-related macular degeneration (AMD) is a multifactorial retinal disease in which genetic susceptibility, aging, metabolic dysfunction, and environmental factors interact to determine disease onset and progression. Although environmental exposures are increasingly recognized as modifiable risk factors for AMD, the molecular mechanisms linking cumulative environmental stress to retinal degeneration remain incompletely understood. In this review, we examine the environmental exposome relevant to AMD and propose oxidative stress as a central molecular link connecting diverse environmental exposures with retinal aging and AMD susceptibility. Epidemiological evidence linking air pollution, particulate matter, cigarette smoke, and other environmental stressors to AMD is reviewed, followed by an analysis of their effects on redox homeostasis and the retinal pigment epithelium (RPE)-Bruch's membrane-choriocapillaris complex. We further discuss how chronic oxidative stress promotes mitochondrial dysfunction, lipid peroxidation, ferroptosis, autophagy and mitophagy impairment, cellular senescence, and senescence-associated inflammation. These processes interact with complement activation, microglial activation, and chronic retinal inflammation, ultimately contributing to RPE dysfunction, choriocapillaris and Bruch's membrane abnormalities, photoreceptor degeneration, and AMD progression. Integrating these mechanisms, we propose an environmental exposome-oxidative stress-retinal aging axis in which cumulative environmental exposures progressively reduce retinal resilience and increase susceptibility to AMD. We also evaluate antioxidant and redox-modulating strategies, including the established evidence for AREDS/AREDS2 supplementation and emerging approaches targeting Nrf2 signaling, glutathione homeostasis, mitochondria, and ferroptosis. Importantly, antioxidant supplementation should not be equated with primary prevention of environmentally induced AMD. Future studies integrating individual exposure monitoring, oxidative stress biomarkers, genetic susceptibility, and retinal phenotyping may enable precision prevention and personalized redox-based interventions. This framework positions environmental exposure as a potentially modifiable driver of retinal biological aging and provides a mechanistic basis for understanding and preventing environmentally driven AMD.

Keywords: age-related macular degeneration; antioxidant therapy; environmental exposome; environmental pollution; ferroptosis; mitochondrial dysfunction; oxidative stress; redox homeostasis; retinal inflammation; retinal pigment epithelium

DOI: https://doi.org/10.3390/antiox15101351

Adv Sci (Weinh). 2026 Oct 28. pii: e78539. [Epub ahead of print]

A Mechanistic Dissection of Multifaceted Complement Attack in Age-Related Macular Degeneration Reveals the Superiority of C3 Inhibition.

Zhidong Chen, Mingshuang Wang, Huiqin Liu, Feng Qian.

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in the elderly, and geographic atrophy (GA) represents its advanced atrophic form. While C5 and C3 inhibitors have shown efficacy in slowing GA progression, the precise pathogenic roles of individual complement effectors and the optimal inhibition strategy remain subjects of ongoing debate. This study employs an in vitro model using A2E-laden retinal pigment epithelium (RPE) cells and normal human serum to systematically investigate complement-mediated RPE degeneration and compare the protective effects of different complement-targeting strategies. We demonstrate that C5 blockade, while preventing lytic cell death caused by the membrane attack complex (MAC), fails to fully restore mitochondrial function or prevent phagolysosomal damage. Crucially, these C5-independent pathologies involve C3 activation products. In contrast, upstream C3 inhibition comprehensively protects RPE cells by ameliorating these diverse pathological processes. Our findings provide a detailed mechanistic understanding of complement-driven RPE degeneration and support a mechanistic rationale for an upstream C3-targeting strategy in GA secondary to AMD.

Keywords: age‐related macular degeneration (AMD); complement C3; complement C5; geographic Atrophy (GA); retinal pigment epithelium (RPE)

DOI: https://doi.org/10.1002/advs.78539

Antioxidants (Basel). 2026 Oct 14. pii: 1328. [Epub ahead of print]15(10):

ATF4 Activation Promotes All-trans-Retinal-Driven Retinopathies in Mice.

Kunhuan Yang, Chaofeng Yu, Danxue He, Lei Tao, Bo Yang, Yuling Chen, Jingmeng Chen, Yalin Wu.

Impaired clearance of all-trans-retinal (atRAL) during the visual cycle leads to retinal degeneration, which is closely associated with autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (dry AMD). Transient activation of activating transcription factor 4 (ATF4) generally supports cellular adaptation to stress, whereas excessive ATF4 expression or prolonged activation can become maladaptive and promote oxidative and metabolic disturbances. Here, we reported that activation of ATF4 promoted atRAL-induced photoreceptor damage through mitochondria-caspase/DNA damage-dependent apoptosis and gasdermin E (GSDME)-dependent pyroptosis and apoptosis, and identified ATF4 as an upstream transcriptional regulator of GSDME. Genetic ablation of Atf4 or pharmacological attenuation of ATF4 signaling with the integrated stress response inhibitor ISRIB visibly preserved the viability and morphology of atRAL-treated 661W cone photoreceptor cells. Both interventions lowered GSDME N-terminal fragment (GSDME-N) abundance, decreased intracellular and mitochondrial reactive oxygen species (ROS) production, and blunted damage to mitochondria and DNA. Notably, pharmacologically suppressing ATF4 expression in the neural retina effectively prevented retinal function loss and structural injury as well as photoreceptor apoptosis and pyroptosis in light-exposed Abca4-/-Rdh8-/- mice, which exhibit severe defects in atRAL clearance and recapitulate key features of STGD1 and dry AMD. Our findings demonstrate that ATF4 is a critical mediator of atRAL-induced retinal atrophy, suggesting that ATF4 inhibition represents a promising therapeutic strategy for STGD1 and dry AMD.

Keywords: ATF4; GSDME; Stargardt disease; macular degeneration; mitochondria

DOI: https://doi.org/10.3390/antiox15101328

Antioxidants (Basel). 2026 Oct 02. pii: 1273. [Epub ahead of print]15(10):

Astaxanthin and Related Carotenoids as a Dual Modulator of Nrf2 and NF-κB in Bisretinoid-Induced Retinal Damage: Mechanistic Rationale and Evidence Gaps.

Babita Kumari Baniya, Hye Jin Kim.

The retinal pigment epithelium (RPE) plays a key role in age-related macular degeneration (AMD). With aging, bisretinoids such as A2E accumulate in RPE lysosomes, and this accumulation is markedly accelerated by ABCA4 loss of function, which impairs the clearance of retinaldehyde from photoreceptor disc membranes. A2E acts as a blue-light photosensitizer, generating reactive oxygen species that cause oxidative stress, lysosomal impairment, and mitochondrial dysfunction. This oxidative burden disrupts the balance between Nrf2-mediated antioxidant defense and NF-κB-driven inflammation. Astaxanthin, a marine-derived xanthophyll carotenoid, may regulate this balance by activating Nrf2/ARE-mediated cytoprotective responses and suppressing NF-κB-dependent inflammation. This review summarizes mechanistic, preclinical, and clinical evidence for astaxanthin's protective effects on RPE cells, with emphasis on bisretinoid-induced retinal injury. Astaxanthin reduces oxidative stress, inhibits NF-κB activity, and enhances Nrf2-dependent antioxidant defenses in hydrogen peroxide-, light-, and ischemia-induced retinal damage; however, because these models do not directly reproduce A2E-mediated phototoxicity, A2E-specific protection remains an untested hypothesis. Standardized A2E-specific models are needed to determine whether these protective effects extend to A2E and its photoproducts. Clinical evidence is also limited and largely based on multi-carotenoid formulations, which prevents the isolation of the effects of astaxanthin.

Keywords: A2E; NF-κB; Nrf2; age-related macular degeneration; astaxanthin; bisretinoid; retinal pigment epithelium

DOI: https://doi.org/10.3390/antiox15101273

iScience. 2026 Nov 20. 29(11): 117957

Factor H polymorphism elevates granzyme B and impairs complement inhibition in human and mouse models.

Harshini Chakravarthy, Jeanne Xi, Hyung-Suk Yoo, Andrew Buss, Boaz Li, Robert Bell, Anne Haegert, Stephane Le Bihan, David J Granville, Joanne A Matsubara.

The complement factor H (CFH) Y402H polymorphism is a leading genetic risk factor for age-related macular degeneration (AMD). Here, we identify extracellular granzyme B (GzmB) as a crucial mediator connecting complement dysregulation to structural pathology. In non-AMD human donor eyes, the high-risk CFH genotype was associated with increased GzmB-positive choroidal mast cells, membrane attack complex deposition, and distinct vitronectin redistribution. Using in vitro human retinal pigment epithelium (RPE) cells, we demonstrate that complement fragment C5a triggers GzmB secretion and zonula occludens-1 disruption. RNA sequencing of GzmB-stimulated RPE cells confirmed transcriptomic signatures of barrier dysfunction and cellular stress. Furthermore, GzmB-deficient mice displayed preserved choroidal vitronectin compared with wild-type controls, supporting a role for GzmB in cleaving this terminal complement inhibitor. These findings delineate a pathogenic C5a-GzmB pathway compromising extracellular matrix integrity, implicating extracellular GzmB as a critical downstream mediator linking genetic risk to early AMD onset.

Keywords: ACVRL1; CASP14; ELAVL1; cervical cancer; targeted therapy

DOI: https://doi.org/10.1016/j.isci.2026.117957