Curcumol targets the FTO/MAFG-AS1 axis to alleviate diabetic retinopathy via epigenetic remodeling and nanodelivery-based microenvironment modulation

Table 1 Main molecular targets and mechanisms of action of curcumol

Molecular target	Normal function	Changes in DR	Regulatory effect of curcumol	Downstream pathological impact	Ref.
FTO protein	m6A demethylase; regulates RNA stability and expression	Abnormal expression under high-glucose conditions; significantly elevated in fibrovascular vitreous membranes of proliferative DR patients	Increases FTO expression, activating its demethylase activity	Stabilizes MAFG-AS1 expression, inhibits endothelial inflammation and vascular leakage	Rong et al[1]
MAFG-AS1	Long non-coding RNA involved in metabolism and inflammation regulation	Increased m6A modification and decreased stability under high-glucose conditions	Stabilizes MAFG-AS1 through FTO-mediated demethylation	Suppresses high glucose-induced endothelial proliferation, migration, and inflammation	Rong et al[1]
Histone lactylation	Epigenetic modification regulating gene expression	Lactate-mediated histone lactylation upregulates FTO expression	Possibly indirectly regulates FTO expression via modulation of histone lactylation	Forms a more complex epigenetic regulatory network, influencing retinal vascular integrity	Chen et al[6]
Inflammatory cytokines	Mediate immune responses and tissue repair	Elevated pro-inflammatory cytokines (TNF-α, IL-6), triggering chronic inflammation	Downregulates IκBα, cyclooxygenase-2, prostaglandin E2, and multiple interleukins	Reduces retinal inflammation, protecting retinal neurons and vascular function	Franzone et al[50]
Blood-retinal barrier components	Maintain homeostasis in the retinal microenvironment	Reduced cadherin and tight junction protein ZO-1 expression, impairing barrier function	Restores endothelial-specific cadherin and ZO-1 expression	Reduces vascular leakage, protecting retinal neurons from damage	Chen et al[6]

DR: Diabetic retinopathy; IL-6: Interleukin-6; m6A: N6-methyladenosine; TNF-α: Tumor necrosis factor-alpha; ZO-1: Zonula occludens-1.

Table 2 Cell type-specific effects within the retinal microenvironment

Cell type	Normal function	Pathological changes in DR	Interaction with other cells	Response to curcumol	Therapeutic significance
Retinal vascular endothelial cells	Maintain blood-retinal barrier, regulate vascular permeability	Abnormal proliferation, increased migration, decreased tight junction proteins	Reduced interaction with pericytes, enhanced interaction with microglia	Inhibits proliferation and migration, restores tight junction protein expression	Primary therapeutic target; improves vascular function, reduces leakage
Pericytes	Maintain capillary stability, regulate blood flow	Reduced number, impaired function, decreased contact with endothelial cells	Disrupted communication with endothelial cells, causing vascular instability	Improves pericyte-endothelial interaction, stabilizes microvascular structure	Protective therapeutic target; preventing pericyte loss is critical
Microglia	Immune surveillance, neuroprotection, synaptic pruning	Increased activation, morphological changes, elevated Iba-1 expression	Release inflammatory cytokines affecting endothelial cells and neurons	Suppresses activation, reduces neuroinflammation, protects neuronal function	Emerging therapeutic target; modulates neuroinflammation
Müller glial cells	Structural support, ion homeostasis, metabolic support	Activation, increased GFAP expression, release of VEGF and inflammatory cytokines	Metabolic support for all retinal cell types	Attenuates glial activation, reduces VEGF expression	Important regulatory target; maintains overall retinal homeostasis
Retinal ganglion cells	Visual signal transmission, visual information integration	Dysfunction, axonal degeneration, increased apoptosis	Affected by microglial inflammation and Müller cell dysfunction	Reduces oxidative stress damage, protects neuronal survival	Neuroprotective target; prevents irreversible vision loss
Retinal pigment epithelium	Outer blood-retinal barrier, supports photoreceptors	Barrier impairment, pigmentary changes, lipid deposition	Interacts with photoreceptors and choroidal vessels	Enhances antioxidant capacity, maintains epithelial integrity	Adjunct therapeutic target; preserves overall retinal function

DR: Diabetic retinopathy; GFAP: Glial fibrillary acidic protein; Iba-1: Ionized calcium-binding adapter molecule 1; VEGF: Vascular endothelial growth factor.

Table 3 Epigenetic regulation-based prevention strategies for diabetic retinopathy

Prevention level	Target population	Intervention strategies	Epigenetic targets	Expected outcomes	Implementation challenges
Primary prevention (prevent onset)	All diabetic patients	Glycemic control, lifestyle optimization (diet, exercise), early screening	Blocking formation of metabolic memory, preventing epigenetic dysregulation	Significant reduction (30%-40%) in DR incidence	Patient compliance, difficulty in long-term adherence
Secondary prevention (high-risk groups)	Patients with diabetes > 5 years or with epigenetic risk markers	Early curcumol intervention, targeted nutritional supplementation, intensive glycemic control	FTO/MAFG-AS1 axis regulation to inhibit epigenetic abnormalities	Delayed DR onset, alleviation of initial symptoms	Accurate identification of high-risk groups, long-term safety of preventive drugs
Tertiary prevention (early-stage DR)	Patients with mild-to-moderate non-proliferative DR	Curcumol combined with anti-VEGF therapy, microenvironmental regulation	Coordinated intervention in multidimensional epigenetic networks	Halting DR progression, prevention of vision loss	Drug interactions in multi-target combination therapies
Early biomarker detection	Regular screening of diabetic patients	Early diagnostic models based on lncRNA-miRNA-mRNA networks	Epigenetic markers such as FTO/MAFG-AS1, miR-125b-5p/SphK1	Early DR risk detection (2-3 years in advance)	Technical complexity of assays, standardization issues
AI-assisted risk assessment	Newly diagnosed diabetic patients	AI prediction systems integrating clinical data and epigenetic biomarkers	Multi-layered epigenetic modification pattern analysis	Personalized risk evaluation, prediction accuracy > 85%	Data privacy, algorithm interpretability, physician-patient acceptance
Metabolic memory intervention	Patients with significant glycemic fluctuations	Specific epigenetic-modifying drugs to reset metabolic memory	DNA methylation, histone lactylation, m6A modification	Disruption of metabolic memory, prevention of ongoing complications	Defining optimal intervention window, individualized treatment planning

AI: Artificial intelligence; DR: Diabetic retinopathy; lncRNA: Long non-coding RNA; m6A: N6-methyladenosine; mRNA: Messenger RNA; VEGF: Vascular endothelial growth factor.

Table 4 Comparison of nano-delivery systems applied in curcumol treatment

Delivery system	Composition	Mechanism of action	Retinal targeting efficiency	Advantages	Limitations
Conventional oral administration	Raw curcumol or tablets	Absorbed via gastrointestinal tract, systemic distribution	Very low; difficulty penetrating blood-retinal barrier	Convenient administration, high patient compliance	Low bioavailability, hepatic first-pass effect, insufficient retinal concentrations
Intravitreal injection	Curcumol solution	Direct ocular administration, high local concentration	High; direct targeting of retina	Rapid onset, high local drug concentration	Invasive procedure, risk of complications, repeated injections needed
PLGA nanoparticles	PLGA, curcumol	Controlled-release system, extends drug half-life	Moderate; passive targeting	FDA-approved, biodegradable, encapsulation efficiency > 90%	Complex preparation, batch-to-batch variability
Liposomes	Phospholipid bilayer, curcumol	Enhanced cell membrane fusion and uptake	Moderate; surface modifications possible for improved targeting	Can carry both hydrophilic and hydrophobic drugs	Limited stability, strict storage conditions
Macrophage membrane-coated nanoparticles	Macrophage membrane, polymer core, curcumol	Inherits homing capability and immune evasion of source cells	High; specific recognition via membrane surface proteins	Active targeting to inflammatory sites, prolonged retention	Complex preparation technology, challenging scale-up production
Dendrimers	Branched polymers, curcumol	High drug-loading capacity, controlled release	Moderate to high; modifiable with various targeting ligands	Precise branched structure, multifunctionality	Potential toxicity, poor biodegradability

FDA: Food and drug administration; PLGA: Poly (lactic-co-glycolic acid).