Cataract: Surgery first - is there still room for basic research?

Abstract

Background

Cataract is the leading cause of blindness worldwide, with surgery being the only effective treatment. Driven by advanced techniques and innovative functional intraocular lenses (IOLs), cataract surgery has achieved a remarkable paradigm shift from vision restoration to refractive surgery. This dominance of surgery raises a core question: Is there still room for basic research?

Main text

Basic research remains vital to addressing unmet challenges in cataract care. The lens serves as an ideal biological model for studying fundamental processes. In addition, efforts to enable cataract prevention and early intervention focus on investigating its etiology, including genetic susceptibility and environmental exposure. Pharmacological research investigates potentials for delaying or even reversing early-stage lens opacification. For intraocular lens (IOL) performance enhancement, advances in material science boost biocompatibility of IOLs, while insights from lens biomechanics further refine IOL design for better long-term stability. To address posterior capsule opacification (PCO), a key postoperative issue, efforts center on developing drug-coated IOLs and sustained-release delivery systems. Lastly, lens regeneration research explores activating residual lens epithelial cells (LECs) for in situ regeneration and tackles challenges in culturing functional lens tissue in vitro.

Conclusions

The success of cataract surgery does not diminish the value of basic research. Instead, collaboration between clinicians and basic researchers, along with increased investment in basic research, will drive breakthroughs in cataract prevention and treatment, enabling natural, long-term vision beyond just clear sight.

1. Introduction

Cataract, as the leading cause of blindness worldwide, imposes a significant epidemiological burden. According to statistics, the number of prevalent cataract cases rose dramatically from 32.8 million in 1990 to 82.2 million in 2021.¹ In low- and middle-income countries, cataract accounts for approximately 50% of blindness causes, while this proportion is merely 5% in developed countries.² With the acceleration of global aging, the affected population continues to expand, highlighting its profound impact on public health and individual quality of life.^1,2

Currently, surgery remains the only effective treatment for cataract, and no pharmacological treatment can reverse lens opacification.^3,4 After decades of development, cataract surgery has achieved a remarkable paradigm shift from "vision restoration" to "refractive surgery". The revolutionary development of phacoemulsification by Charles Kelman fundamentally minimized surgical incisions and enabled rapid visual recovery.⁵ Even in resource-constrained developing countries, manual small-incision cataract surgery (MSICS) is widely used for its low cost and reliable efficacy.⁶ In recent years, femtosecond laser-assisted cataract surgery (FLACS) has emerged as an advanced modality that enables precise capsulotomy, lens fragmentation, and arcuate keratotomy, offering enhanced efficacy, safety, precision, predictability, and repeatability compared to conventional cataract surgery.⁷ Notably, emerging non-ultrasound technologies, such as novel mechanical oscillation systems represent the latest innovation in lens fragmentation, promising to further minimize thermal injury and endothelial trauma.⁸ Furthermore, the integration of intraoperative navigation and imaging systems has further optimized the surgical workflow.⁹

Since Sir Harold Ridley's implantation of the first IOL in 1949, the revolution of IOL technology has been the core driving force behind the transformation of cataract surgery.¹⁰ Early monofocal IOLs could only meet visual needs at a single distance, leaving patients dependent on glasses for near or intermediate vision. Nowadays, multi-functional IOLs cover multi-scenario visual needs. For instance, trifocal IOLs, with their unique diffractive design, simultaneously optimize far, intermediate, and near vision.¹¹ Extended depth-of-focus (EDOF) IOLs, through a continuous focal length design, focus on improving near or intermediate visual quality while maintaining good far vision.¹² Toric IOLs can specifically offset pre-existing corneal astigmatism, greatly enhancing visual quality.¹³

Thanks to these technological leaps, surgical indications have expanded to various populations. Traditional cataract surgery focuses on eliminating lens opacification, while refractive cataract surgery centers on personalized visual needs beyond disease treatment.¹¹ For example, lens extraction has been an important management strategy for angle-closure glaucoma.¹⁴ Refractive lens exchange (RLE) is increasingly used for patients with high refractive errors and presbyopia. These expansions not only shift surgery from treating disease to enhancing visual quality, but also make cataract surgery a comprehensive solution for visual problems in middle-aged and elderly populations. However, controversies lie in whether the benefits outweigh its inherent risks. Clear indications, rigorous informed consent, and careful weighing of surgical risk should be addressed.¹⁵

As cataract surgery becomes highly mature and effective, a core question emerges: Is there still value and room for basic research? The answer is affirmative. The value of basic research extends far beyond the development of cataract therapies. Key issues such as lens model study, etiology of cataract, prevention and treatment of posterior capsular opacification (PCO), and the key regulatory mechanism of lens regeneration and stem cell differentiation still require breakthroughs in basic research, leaving important room for the continuous advancement of the cataract field.

2. The lens as a biological model

The ocular lens represents a highly informative biological model due to its advantages of simplicity, transparency, and unique developmental properties.¹⁶ Its simple architecture allows for the study of key molecular processes related to epithelial-mesenchymal transition (EMT), cellular differentiation, protein aging and aggregation, autophagy, and cataract formation mechanisms.¹⁷

Unlike complex parenchymal organs, the lens epithelium is an avascular, encapsulated monolayer. This unique anatomical simplicity makes it a remarkably tractable model for studying EMT in vivo, which closely mimics cataract and PCO formation.¹⁸ Research utilizing the lens model has clarified key mechanisms regulating EMT, including the TGF-β/Smad signaling cascade, Wnt/β-catenin pathway, RhoA/ROCK/MRTF-A signaling, and PERK axis18, 19, 20. For instance, injury or TGF-β exposure in mouse lenses reliably induces EMT, characterized by the upregulation of α-SMA, vimentin, and fibronectin, and the downregulation of E-cadherin.²¹ Transgenic mouse models allow for the precise manipulation of genes targeting TGF-β or modulating cytoskeletal and stress pathways to study EMT initiation, progression, and inhibition in vivo.^18,22,23 These models serve as powerful and versatile tools for dissecting EMT mechanisms and evaluating potential therapies for cataract and lens fibrosis.

The ocular lens also offers an unparalleled model for investigating the molecular mechanisms of protein aging and aggregation. Among the longest-lived proteins in the human body, the lens crystallins undergo minimal turnover after early development, maintaining solubility and transparency for the entire lifespan.²⁴ For instance, the ocular lens is an ideal model for studying age-related post-translational modifications (PTMs), such as deamidation, truncation, oxidation, phosphorylation, and glycation24, 25, 26. Insights from lens PTMs studies inform not only cataract research but also broader questions of protein aging and aggregation in other tissues. Regarding protein aggregation, several mechanisms including amyloid fibril formation, amorphous aggregation, and high molecular weight (HMW) complex formation have been elucidated, providing potential pathological commonalities with neurodegenerative disorders25, 26, 27. Furthermore, the lens serves as a critical model for studying molecular chaperone biology, specifically the function of α-crystallin. The α-crystallins in the lens function as ATP-independent molecular chaperones, preventing the aggregation of other lens proteins and maintaining transparency.^28,29

To achieve optical transparency, organelles are systematically eliminated to form the organelle-free zone (OFZ) during lens fiber cell differentiation.³⁰ The lens presents a spatiotemporal regulation of differentiation, integrating both autophagy-dependent and -independent mechanisms.^30,31 Recent studies utilizing the lens model have elucidated key molecular players in this pathway, such as HIF1, PI3K/Akt, and JNK-mTORC1 pathways, distinguishing it from starvation-induced autophagy.^31,32 In addition, recent discoveries have highlighted the role of PLAAT-family phospholipases in directly mediating organelle membrane rupture and degradation, independent of classical autophagy.³³ Thus, the lens provides critical insights into studying organelle clearance, oxidative stress, and autophagy.

The developing lens also provides essential signals that regulate the development of adjacent ocular structures such as the cornea, iris, ciliary body, and retina, making it a powerful model for studying tissue-tns induction, fiissue interactions and organogenesis.¹⁶ The lens functions as a dynamic source of growth factor signaling, including TGF-β, BMPs, and FGFs, which are essential for leber differentiation, and tissue morphogenesis.³⁴ Furthermore, the lens also modulates Wnt/β-catenin and Notch signaling and key transcription factors, which are critical for anterior segment patterning and cell fate decisions.^34,35 Taken together, these features position the lens as far more than a passive target of age-related opacity, but a powerful in vivo model for several fundamental biological processes.

3. Exploring etiology: from genes to mechanisms

Cataract is not simply a process of lens protein denaturation caused by aging, but a complex pathological process driven by the combination of genetic susceptibility, environmental exposure, and cellular metabolic disorders.^34,36,37 Although clinical treatment of cataract still mainly relies on surgical removal of the opacified lens, a deeper understanding of these etiological mechanisms is important to identify upstream targets for non-surgical intervention.

Genetic susceptibility is the central etiologic mechanism, particularly for congenital and pediatric cataracts. Over 100 mutations have been linked to congenital cataract, primarily affecting crystallins, connexins, membrane proteins, and transcription factors.³⁶ For instance, mutations in CRYAA and CRYAB generally destabilize the protein structure and promote aggregation, leading to nuclear cataract.³⁸ Similarly, mutations in gap junction genes such as GJA3 and GJA8 impair intercellular communication and trigger autophagy.³⁹ In age-related cataract, large-scale genome-wide association studies have identified 101 independent genetic loci involving in key pathways such as lens development (FOXE3, PAX6), lipid metabolism (GNL3, METTL21A), and oxidative stress response (NFE2L2).⁴⁰ It has been found that most variants are regulatory or mild protein changes that lead to gradual aggregation and increase susceptibility to environmental insults.^40,41

Gene-environment interactions are particularly important in age-related cataract, where genetic variants often increase susceptibility to oxidative, ultraviolet (UV), or metabolic stress rather than causing cataract directly. For example, individuals carrying specific risk alleles have a 2-3-fold higher risk of cataract after UV exposure, and early strengthening of UV protection can significantly reduce the pathogenic effect of environmental exposure.³⁷ Ambient air pollution, particularly PM2.5, emerges as a potent environmental modifier of cataract risk. In experimental models, PM2.5 exposure induces equatorial vacuolation, iron accumulation, glutathione depletion and lipid peroxidation, while lens epithelial cells (LECs) exhibit reduced viability, impaired migration and ferroptotic features. Human capsule transcriptomes from high-PM regions further reveal dysregulation of ferroptosis-related genes such as GPX4, STEAP3, with corresponding changes in iron handling and intercellular antioxidant defense. These findings outline a mechanistic link whereby particulate exposure drives iron-dependent lipid peroxidation and ferroptosis, accelerating cataractogenesis in susceptible individuals.⁴²

The lens's unique metabolic landscape offers distinct targets for intervention. Altered glucose metabolism is critical in both age-related and diabetic cataractogenesis. Excess glucose is diverted into the polyol pathway, leading to sorbitol accumulation, NADPH depletion, and increased advanced glycation end products (AGEs), which together cause osmotic and oxidative stress.⁴³ Elevated aldose reductase (AR) activity has been demonstrated to accelerate cataract formation in transgenic mice overexpressing AR were more susceptible to diabetic cataract, and rats with AR knockdown were more resistant to high-glucose stimuli, with less lens opacification.^44,45 Abnormal lipid metabolism affects both lens structure and signaling, and has been proved to be strongly linked to congenital, diabetic, and age-related cataracts. Lanosterol synthase (LSS), which is a key cholesterol-pathway enzyme in LECs, has been largely investigated over decades. Mutations in LSS lead to lanosterol deficiency in the lens, which not only disrupts the hydrophobic barrier function of the lens membrane, but also affects α-crystallin's chaperone ability to dissolve crystallin aggregates, ultimately causing opacification.^46,47 Another study found that overexpressing LSS or adding lanosterol suppresses Smad2/3 activation, EMT markers, apoptosis, and fibrotic plaque formation, helping preserve transparency.⁴⁷ Although enhancing LSS-lanosterol signaling protects lens cells and can reverse cataracts in several animal models, its potential for preventing human age-related cataracts still requires rigorous evaluation.⁴⁸

Beyond genetic and metabolic insults, mechanical force also function as a potent driver of cataractogenesis. The lens is a mechanically active organ, and accommodation and age-related structural changes concentrate stress at the pre-equatorial or germinative zone.⁴⁹ Finite-element modeling and stretch assays show that such stress activates the mechanosensor PIEZO1, a mechanosensitive cation channel.⁵⁰ Although sustained PIEZO1 signaling may promote LECs senescence and proteostatic collapse, there is no direct in vivo evidence that PIEZO1 mutation or modulation can cause or prevent cataract.⁵¹ Taken together, these findings illustrate that cataractogenesis is not a singular event but a convergence of several mechanisms, providing multiple distinct targets for therapeutic intervention.

4. Pharmacological treatment: prevention vs. reversal

Currently, cataract treatment in clinical practice remains dominated by surgery. Consequently, pharmacological intervention targeting the core pathological mechanisms of lens opacification provides an important research direction for delaying cataract progression or reversing established opacities.^46,52

Imbalanced oxidative stress is the key driver of cataract formation, and antioxidants are an early-studied intervention category, which function by scavenging reactive oxygen species (ROS) and enhancing the endogenous antioxidant system.⁵³ For example, N-acetylcysteine and its liposomal formulations have demonstrated efficacy in boosting endogenous glutathione levels and inhibiting oxidative damage.^54,55 Similarly, natural compounds like resveratrol and curcumin have shown efficacy by activating the SIRT1 pathway to downregulate p53-mediated apoptosis and reduce inflammatory cytokines.^56,57 Furthermore, metformin has also been confirmed to reduce LECs apoptosis and crystallin aggregation by inhibiting oxidative stress and promoting autophagy, showing a protective effect in diabetic cataract models.⁵⁸ Nevertheless, antioxidants offer limited benefit for congenital cataracts, which are primarily caused by genetic mutations rather than oxidative stress.⁵⁹ For congenital cataracts in clinical settings, immediate optical clearance is mandatory to prevent irreversible amblyopia. Furthermore, large-scale randomized controlled trials and observational studies have shown no significant benefit of antioxidant supplementation in preventing cataract progression in general populations, highlighting a significant research gap for future clinical trials.⁶⁰

Abnormal aggregation of crystallins is the final common pathway of lens opacification. Anti-aggregation compounds have become a key strategy for reversing early opacification by disrupting aggregate structures or inhibiting aggregation initiation.^59,61 For instance, lanosterol was initially proposed to dissolve protein aggregates in animal models, while subsequent studies failed to replicate these effects in human lenses.^48,62 Furthermore, lanosterol synthase activity is primarily localized in the endoplasmic reticulum, making direct interaction with crystallin aggregates unlikely.⁶³ Alternatively, small-molecule chaperones, which bind and stabilize crystallin proteins, have been shown to reverse aggregation of α-crystallins and restore lens transparency in ex vivo mouse models.⁶⁴ These agents work by stabilizing the native, soluble forms of crystallins, thereby reducing amyloid and amorphous aggregate formation.⁶⁴ However, most evidence remains limited to in vitro or animal studies, and robust clinical trials in humans are lacking.

Regardless of the pharmacological treatment, the avascular nature of the lens and the blood-aqueous barrier pose significant challenges on delivery.^55,65 Currently, delivery systems such as nano-micelles and in-situ gels can increase drug concentration in the lens, laying a foundation for clinical translation.^55,65 In the future, combining precise delivery technology with in-depth mechanism research is expected to provide a new strategy for non-surgical intervention of cataract.

5. IOL performance and capsular biocompatibility

As the core device for visual recovery after cataract surgery, the optimization of IOLs relies on dual breakthroughs in materials science and lens biomechanics.^66,67 The development of IOL materials has always focused on addressing the limitations of traditional materials, aiming to improve capsular biocompatibility, optical performance, and mechanical properties (Table 1). Polymethyl methacrylate (PMMA), the first clinically applied IOL material, exhibits excellent optical transparency and stability, but its rigid structure requires large surgical incisions.⁶⁸ To overcome these limitations, silicone and acrylics materials have ushered in the era of foldable IOLs. Silicone IOLs are highly flexible and transparent, but are more prone to PCO and calcification.⁶⁸ Acrylic IOLs are the most widely used implants in cataract surgery, with hydrophobic and hydrophilic variants offering distinct advantages. Hydrophobic acrylic IOLs, characterized by low water content and high refractive index, are typically less prone to develop PCO, but traditional materials may develop glistenings that scatter light.^68,69 Conversely, hydrophilic acrylic IOLs, with higher water content, offer superior biocompatibility and less inflammatory response, but are more susceptible to PCO and calcification or opacification.⁷⁰

Table 1.

Comparative overview of IOLs materials designs.

Category	Material/Design	Key advantages	Limitations
Traditional rigid	PMMA	Rigid; Stable; Biocompatible	Large surgical incisions; Non-foldable
Foldable	Silicone	Foldable; Flexible	Lower refractive index; Risk of calcification
	Hydrophobic Acrylic	Low water content; High refractive index; Less prone to PCO	May develop glistenings (traditional materials)
	Hydrophilic Acrylic	High water content; Superior biocompatibility; Less inflammatory response	More susceptible to PCO; Risk of calcification or opacification
Advanced Materials	Injectable Hydrogels	Lens refilling; Minimally invasive	Stability; Biocompatibility; Lack long-term data
	Light-Responsive IOLs	Postoperative refractive adjustment	Phototoxicity; Infection risk; Lack long-term data
Surface modifications	Drug-eluting coatings	Sustained drug release; Targeted PCO inhibition	Drug toxicity; Limited long-term efficacy and safety profile; Clinical translation limited

Abbreviation: IOLs, intraocular lenses; PCO, postoperative capsular opacification; PMMA, polymethyl methacrylate.

Recent research has achieved breakthroughs through innovative copolymer designs such as injectable hydrogels and light-responsive materials that enable in situ lens formation and accommodation.⁷¹ For instance, thermosensitive hydrogels such as poloxamer-based systems, transition from liquid to gel at body temperature, allowing minimally invasive delivery and in situ molding of a full-size lens.^71,72 Photo-crosslinkable hydrogels, using blue or UV light, enable rapid curing and precise control over lens shape and mechanical properties.^71,72 Additionally, some materials incorporate photoactive groups that allow post-implantation adjustment of refractive index or shape using specific wavelengths of light, enabling non-invasive adjustment of lens power postoperatively.⁷³ However, concerns regarding long-term stability, safety, phototoxicity, and infection risk are warranted to be addressed.⁷⁴ Though light-adjustable IOLs are clinically available and have shown safe and stable results, careful patient selection and longer follow-up periods are needed for optimal outcomes.⁷⁵

Surface modification technologies further expand the functional capabilities and biocompatibility of IOLs. For example, the incorporation of antiproliferative drugs or antibiotics into the IOL surface allows for sustained release to inhibit LECs proliferation and inflammation.⁷⁶ Photodynamic and photothermal coatings use photosensitizers or photothermal agents to selectively target LECs and inhibit PCO formation.⁷⁷ Recent research has also focused on nanotechnology-enabled coatings, enzyme-triggered drug release, and gene delivery systems.^78,79 However, the translation of these advances into routine clinical practice remains limited, necessitating further validation to ensure safety and sustained efficacy.⁸⁰ Although some heparin-modified IOLs have shown efficacy in reducing early postoperative inflammation and cell deposits, no significant long-term differences in PCO have been observed compared to unmodified IOLs.⁸¹ Therefore, long-term, large-scale studies are needed to confirm sustained benefits and broader clinical adoption.

Age-related changes in lens biomechanics are central to the development of presbyopia and cataracts, while advances in measurement techniques and modeling have deepened our understanding of lens function and informed IOL design.⁸² Lens biomechanics plays a pivotal role in maintaining dynamic adaptation between the IOLs, the capsular bag and the zonular apparatus, which largely determines IOL centration, tilt, and rotation. Research has been focused on IOL haptic geometry and design to improve the capsular interaction and stability over time, offering predictable effective lens position. For instance, plate-haptic hydrophilic IOLs show earlier and more complete capsular adhesion than C-loop designs, which may inhibit PCO and achieve less tilt and decentration, although plate-haptic IOLs generally adapt poorly to capsular bag contraction.⁸³ For Toric IOLs, optimized or frosted haptics and appropriate geometry achieve excellent rotational stability, improving refractive outcomes.⁸⁴ Recent developments in accommodating IOLs have introduced shape-changing and refractive index-modulating designs powered by capsule stretch or internal stimulators.⁸² Gel or fluid-filled designs can achieve accommodation by adjusting gel thickness and refractive index, potentially altering refractive power change.⁸⁵ Despite promising preclinical biomechanics, there remain substantial barriers towards clinical translation.

6. Targeting PCO

PCO is the one of the most common complications following cataract surgery, with an incidence of 5%–20% within 3 years postoperatively, severely impairing patients' postoperative visual quality.⁸⁶ While Nd:YAG capsulotomy is the standard treatment, it is associated with transient or chronic intraocular pressure elevation, glaucoma, cyctoid macular edema, and an increased risk of retinal detachment, especially for patients with comorbidities such as uveitis, diabetic retinopathy, and preexisting glaucoma.⁸⁷ Furthermore, Nd:YAG also imposes high costs on patients and consumes clinical resources, creating high socioeconomic burden.⁸⁷ Therefore, in-depth analysis of the pathogenesis of PCO and the development of efficient and safe pharmacological strategies are critical topics in current basic research.

PCO arises from a normal wound-healing response triggered by surgical injury, where residual LECs respond to the trauma rapidly, initiating a robust cascade of proliferation, migration, EMT, differentiation, and extracellular matrix (ECM) remodeling.⁸⁶ It can be divided into fibrotic and regenerative subtypes, which differ in onset timing and regulatory mechanisms. TGF-β2 is central to fibrotic PCO, inducing EMT via Smad-dependent and independent pathways, leading to myofibroblast transformation and ECM contraction.^21,88 Regenerative PCO, typically emerging later post-surgery, involves aberrant differentiation of LECs, forming Soemmerring's rings or Elschnig's pearls.⁸⁶ A critical challenge in therapeutic development is the "therapeutic trade-off", where inhibiting the TGF-β pathway to suppress fibrosis may inadvertently upregulate FGF signaling, thereby promoting regenerative pearl formation.⁸⁹ Inhibitors of aldose reductase have been observed to both suppress fibrotic PCO and enhance organized lens regeneration in mouse models, highlighting the need for dual inhibition strategies.^44,89

Surgical optimization also plays an irreplaceable role in PCO prevention, particularly through mechanical blockade of LECs migration. For instance, in pediatric cataract surgery, a primary posterior capsulorhexis is routinely performed to prevent visual axis obscuration.⁹⁰ This efficacy can be further augmented by posterior optic capture, a well-established alternative to posterior capsulorhexis with anterior vitrectomy.⁹¹ Furthermore, innovative IOL designs such as the "bag-in-the-lens" utilizes this principle by requiring a posterior capsulorhexis to support the lens, thereby creating a closed system that completely mechanically prevents PCO formation.⁹² Compared to pharmacological interventions, these mechanical strategies offer a superior safety profile. However, its application is challenged by the need for advanced surgical skill and strict anatomical requirements for the capsule.

Complementary to these surgical advances, research targeting PCO has been focused on drug-eluting IOLs, controlled drug delivery systems, and the targeted regulation of LECs. Drug-eluting IOLs represent a promising approach for preventing PCO, delivering drugs into the capsular bag through surface modifications such as physical coatings, chemical grafting, or nanocarrier integration to enable prolonged release. For instance, bromfenac-coated IOLs inhibit COX-2 and the MEK/ERK pathway, reducing LECs migration and anterior capsule opacification.⁹³ Antiproliferative or cytotoxic drugs including doxorubicin, paclitaxel, and methotrexate, have been loaded into IOLs to suppress LECs proliferation.⁹⁴ However, short-term in vitro data suggested that uncontrolled release of these drugs into the anterior chamber carried a risk of permanent corneal endothelial damage and retinal toxicity, warranting the development of targeted and dose-limited delivery strategies.⁹⁴ Photo-responsive and near-intrared light-triggered IOLs, combined with photothermal ablation, enabled on-demand release and controlled delivery, thereby improving safety profile.^95,96 Nevertheless, most strategies remain at the preclinical stage, and long-term efficacy and safety evaluations are crucial for clinical translation. In addition, miRNA-based therapeutics targeting SMAD and Notch 1 pathways offer high specificity and low systemic toxicity, but their in vivo delivery remains difficult and require vectors, coatings, or nanoparticles to enhance stability and transfection efficacy.⁹⁷ Besides, the off-target effect in the RNAi system and safety concerns of viral vectors are also significant hurdles to the clinical adoption of these therapies.^98,99

7. Lens regeneration

Lens regeneration offers a new direction for cataract treatment, aiming to transcend the limitations of traditional IOL implantation.^46,100 Compared to IOLs, a regenerated lens has potential to restore full-range visual accommodation and avoids IOL-related complications such as dysphotopsia and PCO. The regeneration of the lens crucially relies on the inherent proliferation and differentiation potential of LECs.^46,100 Crucially, whether residual LECs form PCO or a more transparent structure is mainly determined by the postoperative niche, including the intensity of inflammation, growth factor balance, microenvironment cues, and capsule integrity, and basic research plays a crucial role in revealing the mechanisms of this process and promoting clinical translation.^46,100

LECs exhibit distinct functional heterogeneity depending on their spatial distribution. The LECs beneath the anterior capsule are typically quiescent but represent a label-retaining population with stem-cell potential.⁴⁶ Evidence suggests that upon stimuli, these cells can re-enter cell cycle and differentiate to support would healing process.¹⁰¹ In contrast, the germinative zone (GZ) at the equatorial region contains numerous LECs that retain lifelong proliferative capacity, continuously differentiating into lens fibers.⁴⁶ In mammals, the lens possesses a certain regenerative capacity dependent on the LECs of the GZ. It has been observed that when the rabbit lens is extracted while preserving the capsule, the equatorial region of the capsular bag became filled with lens-like tissues within 3–5 weeks.¹⁰² A similar phenomenon was also observed in the capsular bag of rats one month after lens extraction.¹⁰³ These findings suggest that achieving high-quality in situ regeneration of the lens requires the preservation of LECs, particularly those in the equatorial region.

To preserve more autologous LECs, researchers have refined surgical techniques. Minimally invasive lens surgery (MIST) was performed by preserving the integrity of the lens capsule and lens epithelial stem cells, allowing a new lens to grow in situ.¹⁰⁰ In rabbit models, transparent biconvex lenses formed 7 weeks after surgery, achieving a refractive power of 15.6 diopters, comparable to natural lenses.¹⁰² In macaque models, functionally normal regenerated lenses were also observed 5 months after surgery, without complications such as macular edema or retinal detachment.¹⁰⁰ PAX6 and BMI1 have been identified as essential regulators of LECs renewal, with PAX6 marks and functionally supports lens epithelial progenitors, and BMI1 maintains their long-term proliferative capacity.^100,104 When applying the identical surgical procedure, clinical trials on children under 2 years old with congenital cataracts demonstrated that LECs preserved by MIST can achieve lens regeneration.¹⁰⁰ A transparent biconvex structure was formed by 3 months, and the lens thickness and refractive power were close to normal by 8 months.¹⁰⁰ However, current evidence suggests uncertain visual outcomes compared to well-established surgery combined with optical correction.^105,106 Major concerns include the slow and incomplete regeneration, increasing the risk of amblyopia and secondary surgical intervention. Additionally, as the underlying genetic defects in congenital cataract are not corrected, the regenerated lens faces a risk of re-opacification. For adult cataracts, it is difficult to perform MIST and usually requires phacoemulsification, which can damage LECs. Furthermore, capsular stiffness and the senescent microenvironment also hinder the regenerative capacity of LECs.

Given that the proliferative activity of human LECs decreases with age, age-related cataract patients require a different approach—one that does not rely solely on endogenous LECs. The introduction of exogenous stem cells presents a promising solution. Using pluripotent stem cells, researchers have successfully cultivated transparent, refractive lens organoids in vitro, replicating structures including lens epithelial cells, lens fibers, and capsule-like components.¹⁰⁷ A recent study implanted human embryonic stem cell-derived cells into the lens capsule of rabbit models and observed nearly complete lens regeneration.¹⁰⁶ The regenerated lens reached 85% thickness of that of the contralateral eye and exhibited a biconvex shape, high transparency, and refractive power close to natural lenses. This strategy addresses the limitations of insufficient thickness and poor transparency of lenses regenerated by endogenous LECs.¹⁰⁶

Despite these advances, basic research still faces numerous challenges. Future research should deeply analyze the molecular network regulating LECs proliferation and differentiation, such as the mechanisms maintaining long-term lens transparency. It is also critical to explore strategies to optimize the morphology, optical quality, safety, and long-term function of regenerated lenses, and to develop methods to activate the regenerative potential of adult LECs.⁴⁸ By overcoming these challenges, it is expected to expand the application of lens regeneration from pediatric patients to a broader adult population, creating a new paradigm for cataract treatment.

8. Conclusions

Cataract surgery has achieved a significant leap from vision restoration to refractive optimization after decades of development. PCS has become the global gold standard for cataract treatment, while FLACS further improves precision and efficacy. With the development of various presbyopia-correcting IOLs and the expansion of surgical indications, refractive cataract surgery has become the mainstream choice to meet personalized visual needs and maximize patient satisfaction. However, basic research still holds irreplaceable value. The lens serves as an important biological model for elucidating the etiology of cataractogenesis and fundamental processes like EMT. Moreover, current advances in pharmacological interventions and PCO treatment are expanding the therapeutic landscape, while the exploration of lens regeneration strategies may eventually complement surgical approaches.

In the future, with the interdisciplinary integration of molecular biology, materials engineering, and regenerative medicine with the field of cataract, basic research will accelerate its transition from mechanism analysis to translational application. It is foreseeable that the in-depth integration of basic research with clinical practice will continue to expand the boundaries of cataract treatment strategies, providing more efficient and inclusive solutions for the global burden of cataract.

Study approval

Not Applicable.

Author contributions

The authors confirm contribution to the paper as follows: Conceptualization: YY, QF, and KY; Data collection: YZ and LC; Drafting the manuscript: YZ, LC, and YG; Review and editing: YZ, YY, QF, and KY; Supervision: YY, QF, and KY. All authors reviewed the results and approved the final version of the manuscript.

Editorship disclosure

Given the role as Editor-in-Chief, Ke Yao had no involvement in the peer-review of this article and has no access to information regarding its peer-review.

Funding

The work was supported by the National Natural Science Foundation of China (82471054, 82371036, 82271063, 82201158), Key Research and Development Program of Zhejiang Province (2025C02156, 2025C02157), Central Guidance for Local Scientific and Technological Development Funding Program (2024ZY01057) and Regional Innovation Development Joint Fund of the National Natural Science Foundation of China (U24A20705).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

AGE

advanced glycation end products

AR

aldose reductase

ECM

extracellular matrix

EDOF

extended depth-of-focus

EMT

epithelial-mesenchymal transition

FLACS

femtosecond laser-assisted cataract surgery

GZ

germinative zone

HMW

high molecular weight

IOL

intraocular lens

IOLs

intraocular lenses

LECs

lens epithelial cells

LSS

lanosterol synthase

MIST

minimally invasive lens surgery

MSICS

manual small-incision cataract surgery

OCT

optical coherence tomography

OFZ

organelle-free zone

PCO

posterior capsule opacification

PCS

phacoemulsification cataract surgery

PMMA

polymethyl methacrylate

PTMs

post-translational modifications

RLE

refractive lens exchange

ROS

reactive oxygen species

UV

ultraviolet