Non-visual opsins link violet light to myopia prevention

A narrative review published in Eye and Vision synthesizes emerging evidence that non-visual opsins, specifically OPN3, OPN4, and OPN5, play a critical role in regulating myopia development. The review highlights how these light-sensitive proteins, which function outside the standard visual pathway, may mediate the protective effects of natural sunlight against near-sightedness. By examining the interplay between specific light wavelengths and ocular growth, the authors suggest that these opsins offer a new mechanistic framework for understanding why outdoor time reduces myopia risk. This perspective shifts the focus from simple optical correction to the molecular signaling pathways that drive emmetropization, the process by which the eye achieves normal focus.

In East Asian countries, the prevalence among children and young adults has risen dramatically, reaching up to 90% in recent decades. While low levels of myopia can be corrected with glasses or contact lenses, high myopia carries significant risks of severe visual impairment, including myopic macular degeneration, optic neuropathy, and glaucoma. The review notes that one in three individuals with high myopia will develop a sight-threatening complication, underscoring the urgent need for effective prevention strategies that address the underlying mechanisms of axial elongation.

Current prevention strategies, such as topical atropine, orthokeratology lenses, and multifocal eyeglasses, often face limitations in long-term efficacy and patient adherence. The review points out that the impact of these treatments tends to diminish over time, with the highest benefit observed in the first year of use. This has prompted researchers to investigate the biological cues that guide eye growth, particularly the role of light. Epidemiological studies consistently show that time spent outdoors in natural sunlight is protective against myopia, while indoor time, independent of near work, is a risk factor. The specific wavelengths of light present in sunlight appear to be a key differentiator from artificial indoor lighting.

Among the non-visual opsins, OPN5, also known as neuropsin, has emerged as a primary candidate for mediating the protective effects of violet light. OPN5 shows a maximum absorption at 380 nm, which falls squarely within the violet light range. This wavelength is often filtered out by modern windows and artificial light sources, leading to a potential deficiency in OPN5 activation in indoor environments. The review details studies in mice where stimulation of OPN5-expressing retinal ganglion cells with violet light prevented experimental myopia. When violet light was supplemented in a lens-induced myopia model, it yielded the strongest myopia suppression effect compared to blue, green, or red light at the same irradiance levels.

The mechanism by which OPN5 influences myopia appears to involve the regulation of choroidal thickness and the expression of the gene EGR-1. In mouse models, the selective deletion of OPN5 from the retina resulted in the loss of violet-light-dependent myopia suppression and led to notable choroidal thinning. The choroid, the vascular layer of the eye, is believed to play a major role in axial elongation; its thinning is often a precursor to myopia. Violet light exposure has been shown to maintain choroidal thickness, potentially by expanding the choriocapillaris and ensuring adequate oxygen and nutrient supply to the sclera. This vascular support may prevent the structural alterations that lead to axial elongation and refractive error.

OPN4, or melanopsin, is another non-visual opsin that has received significant research attention, primarily for its role in circadian rhythm regulation. Its peak sensitivity is around 480 nm, in the blue light range. The review discusses conflicting findings regarding OPN4’s role in myopia. Some studies suggest that mice lacking OPN4 show greater myopic shifts in response to form deprivation, implying a protective role for melanopsin in normal refractive development. However, other studies using different ablation methods found reduced axial length and hyperopic refractions in OPN4-deficient mice. These discrepancies highlight the complexity of the underlying mechanisms and the need for further investigation into how melanopsin signaling interacts with other photoreceptor systems.

The relationship between OPN4 and myopia may be mediated through retinal dopamine levels. Dopamine has been implicated in myopia development for over 30 years, with retinal dopamine generally regarded as a cue to cease myopic axial elongation. Studies have shown that supplementation with levodopa, a dopamine precursor, can reduce myopia susceptibility in form-deprivation models. In OPN4-deficient mice, levodopa treatment reduced the induced myopia by half, suggesting that OPN4 influences myopia via dopamine regulation. However, the role of dopamine is nuanced; in some species, pharmacologically reduced dopamine levels did not consistently lead to myopia, and the DOPAC/dopamine ratio may be a more accurate indicator of dopamine turnover than absolute levels alone.

OPN3, or encephalopsin, is the most abundantly expressed non-visual opsin in mammals, yet its role in myopia remains the least understood. OPN3 has a maximum absorption around 465 nm, in the blue light range, and is expressed in a wide range of tissues, including the retina and choroid. The review notes that myopia-related genes, such as Ctgf and Egr-1, show expression changes dependent on OPN3. In lens-induced myopia models in tree shrews and mice, retinal Ctgf expression was significantly downregulated. Interestingly, while retinal deletion of OPN3 did not produce a myopic phenotype, a germline mutation did, suggesting that OPN3’s influence on refractive development may originate from non-retinal tissues. This finding indicates that the mechanisms governing OPN3’s role are distinct from those of OPN4 and OPN5.

The review also explores the potential of light-based therapies derived from these opsin findings. Violet light therapy, which targets OPN5, has shown promise in clinical settings. A study by Torii et al. found that children wearing violet light-emitting eyeglass frames for three hours per day experienced significant changes in choroidal thickness and reduced axial elongation compared to controls. The reduction in axial elongation was modest, around 20% over two years, suggesting that this treatment might be most effective when combined with other established strategies. Similarly, blue light stimulation therapy, which targets OPN4 in intrinsically photosensitive retinal ganglion cells, has been shown to increase choroidal thickness and reduce axial elongation in young adults when applied at the physiological blind spot.

Despite these promising findings, the review emphasizes the limitations of current research. Many studies on spectral interventions are conducted in animal models or involve short-term, non-randomized trials in humans. The durability of these effects over long periods remains to be fully established. Additionally, the complex interplay between different wavelengths, light intensity, and circadian timing makes it difficult to isolate the specific contributions of each opsin. The review calls for more comprehensive molecular analyses and long-term prospective clinical trials to verify the efficacy and safety of light-based therapies. Understanding the precise mechanisms by which non-visual opsins regulate myopia could lead to the development of new lighting regulations, wearable devices, and targeted treatments to mitigate the global rise in myopia.

Beyond direct opsin activation, the review examines longitudinal chromatic aberration as a physical model explaining how chromatic cues direct emmetropization. Because refractive media bend wavelengths differently, short-wavelength light focuses in front of the retina to signal reduced axial elongation, whereas long wavelengths focus behind it to stimulate growth. In experimental testing, viewing images with the blue channel in sharp focus significantly accelerated ocular elongation, while keeping the red channel sharp produced measurable axial shortening. However, the review stresses that such experiments impose artificial open-loop conditions that hold wavelength stimuli static, unlike natural environments where the eye dynamically adjusts through closed-loop feedback. Furthermore, species-specific photoreceptor distributions and interactions between optical defocus and color cues complicate efforts to isolate pure wavelength effects.

The broader biological significance of non-visual opsins is also underscored by OPN5’s involvement in ocular vascular development and circadian regulation. In developing mouse pups, functional OPN5 regulates the regression of hyaloid vasculature necessary to establish a transparent optical axis. Disruption of this pathway alters dopamine levels via the SLC6A3 transporter, suppressing vascular endothelial growth factor receptor 2 activity and causing premature vessel regression. Similar dopamine-mediated vascular dynamics are suspected in humans, where dopamine administration in premature infants correlates with retinopathy of prematurity. In addition, retinal circadian rhythms directly affect ocular development, as seen when disruption of the clock gene Bmal1 produces myopic refraction and axial lengthening. Because OPN5 participates in retinal photoentrainment, the authors note that violet-light exposure timed specifically at dawn may deliver the strongest protective stimulus.

Complementary interventions discussed in the review include repeated low-level red-light therapy and nutritional modulation. Clinical trials evaluating repeated low-level red light in school children demonstrated a 33.4 percent relative reduction in myopia incidence alongside increased choroidal thickness, prompting ongoing randomized trials to assess long-term efficacy. On the biochemical front, researchers have explored dietary agents that stimulate EGR-1, a downstream mediator shared by non-visual opsin signaling. Administering crocetin, a gardenia fruit metabolite that activates EGR-1 in a dose-dependent fashion, mitigated axial elongation, myopic refractive shifts, and choroidal thinning in murine models. Concurrently, human observations indicate that violet-transmissive contact lenses and phakic intraocular lenses slow axial elongation compared to violet-blocking alternatives, especially in young children whose crystalline lenses permit higher ultraviolet and violet transmission.

Subject of Research: The role of non-visual opsins in light-mediated myopia regulation

Article Title: Light and myopia: a focus on the expanding role of non-visual opsins

Article References: Gettinger, K., Tsubota, K., Negishi, K., & Kurihara, T. (2026). Light and myopia: a focus on the expanding role of non-visual opsins. Eye and Vision, 13(1), Article 6. https://doi.org/10.1186/s40662-025-00472-y

Image Credits: AI Generated

DOI: 10.1186/s40662-025-00472-y

Keywords: myopia, non-visual opsins, OPN5, OPN4, OPN3, violet light, choroidal thickness, axial elongation, emmetropization, retinal dopamine, EGR-1, circadian rhythm, ocular growth, light therapy, refractive error, retinal ganglion cells, melanopsin, neuropsin, encephalopsin, myopia prevention