Table 1.

Overview of experimental compounds showing promise in improving diabetic keratopathy.

Molecule	Chemistry/Biologic Effect	Study Design, Route, Model	Molecular Target and Study Outcome	Ref.
β-carotene	vitamin A derivative	in vivo, oral application, diabetic rat model	antioxidant and hypoglycemic effect, ameliorating corneal changes	[139]
calcitriol	vitamin D derivative	in vitro, high glucose-treated human corneal epithelial cells	inhibition of ROS–NLRP3–IL-1β signaling via activation of Nrf2 antioxidant signaling	[143]
		in vivo, topical administration, diabetic mouse model	promotion of diabetic corneal wound healing and reinnervation via NLRP3 suppression	[144]
		in vivo, topical route with 1,25 Vit. D or 24,25 Vit. D, diabetic mouse model	improvement of corneal wound healing	[145]
NAC	N-acetylated derivative of the natural amino acid L-cysteine	in vivo, topical administration, diabetic mouse model	mitigation of ocular surface damage via suppression of the ROS/NLRP3/caspase-1/IL-1β signaling pathway	[146]
ALA	(R)-enantiomer of lipoic acid: vitamin-like fatty acid	in vitro, high glucose-exposed human corneal epithelial cells	suppression of AGE–RAGE–TLR4-NLRP3 pathway-induced inflammation and amelioration of oxidative stress, apoptosis, and inflammation	[147]
		Eye drops based on a combination of ALA and HPMC in diabetic patients with DED	effectiveness in the treatment of diabetic DED and self-regeneration, improving corneal defects	[148]
GLY	naturally occurring saponin	in vitro, in vivo, ex vivo, oral application, diabetic mouse model	downregulation, among others, of HMGB1, IL-1β, TLR2, TLR4, and NLRP3, leading to attenuation of corneal inflammation and oxidative stress	[151]
		in vivo, subconjunctival injection, diabetic mouse model	attenuated activation of RAGE and TLR4 molecular pathways, promoting corneal epithelial wound healing	[47]
VP13/126	DMF derivative	in vitro, glucose-impaired rabbit corneal epithelial cells	activation of the Nrf2/HO-1 pathway, inducing corneal re-epithelialization	[153]
SIRT1 modulators	miRNA	in vivo, subconjunctival injection, diabetic mouse model	miRNA-182 upregulates SIRT1 and downregulates NOX4, promoting diabetic corneal nerve regeneration	[155]
		in vivo, subconjunctival injection, diabetic murine model	blockade of microRNA-204-5p favors corneal epithelial wound healing via SIRT1	[156]
salidroside	glycoside, extract from Rhodiola crenulata, natural antioxidant	in vitro and in vivo, eye drops, DED murine model	mitigation of oxidative stress in DED through Nrf2 via AMPK–SIRT1 signaling on the ocular surface	[157]
rosiglitazone	thiazolidinedione, insulin-sensitizing drug	in vivo, oral gavage, diabetes-related DED in a mouse model	decrease in oxidative stress in the lacrimal gland in part by activating PPARγ, inducing overexpression of antioxidants such as GPx3	[158]
quercetin	flavonol, naturally occurring antioxidant	in vivo, diet route, diabetic mouse model	improvement of tear function in diabetic mice via upregulation of SOD1 and SOD2 in the lacrimal gland, reduction of ROS formation, and promotion of cell survival	[159]
mito-Q	synthetic drug, mitochondria-specific antioxidant	in vivo, diet route, diet-induced obese or type 2 diabetic rat models	amelioration of nerve conduction velocity, corneal and intraepidermal nerve fiber density, corneal sensitivity, and thermal nociception	[162]
NMN	nucleotide	in vitro, high glucose-treated human corneal epithelial cells	enhancement of cell viability by reducing apoptosis, increasing cell migration, and restoring tight junctions via activation of the SIRT1/Nrf2/HO-1 axis	[163]
DNAse I	enzyme responsible for DNA degradation	in vivo, topical administration, diabetic mouse model	improvement of corneal epithelial wound healing and nerve regeneration by activating Akt, IGFR-1, SIRT1, while inhibiting NOX2 and NOX4 upregulation, reducing ROS	[164]
pycnogenol	mixture of flavonoids and procyanidins	in vivo, eye drops, diabetic rat model	acceleration of wound re-epithelialization	[166]
thymosin β-4	naturally occurring polypeptide	in vitro, human corneal epithelial cells exposed to oxidative stress	upregulation of antioxidants such as SOD	[167]
SkQ1	mitochondria-targeted antioxidant	in vivo, topical administration, diabetic mouse model	amelioration of DED severity and diabetic keratopathy via improvement of mitochondrial function	[137]
cemtirestat	aldose reductase inhibitor and antioxidant	in vivo, oral administration, rodent model for glycotoxicity	reduction of inflammation and oxidative stress via TNF-α, IL-1β, NF-kB, and caspase-3 downregulation	[169]
insulin	growth factor with regenerative and antiapoptotic effects	in vitro, human and canine corneal epithelial cells	activation of the PI3K/Akt axis, leading to antiapoptotic effects, favoring cell proliferation and migration, accelerating corneal wound healing	[171]
		in vivo, eye drops, diabetic murine model	enhancement of the corneal nerve repair via activation of the Wnt/β-catenin pathway	[172]
		insulin eye drops in diabetic patients with diverse dose regimens (0.5 or 1.0 unit/drop, 2–4 times daily)	enhancement of corneal epithelial wound healing, mitigation of diabetic DED, improvement of re-epithelialization compared with autologous serum in persistent corneal defects	[174,175,176]
PEDF	growth factor with antioxidant effects	in vivo, topical administration, diabetic mouse model	reduction of corneal epithelial defects via mitigation of ROS generation, decreased RAGE expression, and upregulation of SOD-1	[177]
rhFGF-21	growth factor with anti-inflammatory and antioxidant properties	in vitro on human corneal epithelial cells and in vivo on a diabetic mouse model	promotes corneal epithelial wound healing by reducing pro-inflammatory markers like TNF-α, IL-6, IL-1β and promoting antioxidant enzyme expression such as that of SOD-1	[178]

Table Abbreviations. AGEs: advanced glycated end products; Akt: Ak strain transforming (also known as protein kinase B); ALA: α-lipoic acid; AMPK: adenosine monophosphate-activated protein kinase; DED: dry eye disease; DMF: dimethyl fumarate; GLY: glycyrrhizin; GPx3: glutathione peroxidase 3; HMGB1: high-mobility group protein B1; HO-1: heme oxygenase-1; HPMC: hydroxypropyl methylcellulose; IGFR-1: insulin-like growth factor receptor 1; IL-1β: interleukin beta 1; miRNA: micro RNA; Mito-Q: mitoquinone; NAC: N-acetylcysteine; NF-kB: nuclear factor ‘kappa-light-chain-enhancer’ of activated B cells; NLRP3: nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3; NMN: nicotinamide mononucleotide; NOX: nicotinamide adenine dinucleotide phosphate oxidase; Nrf-2: nuclear factor erythroid-derived 2-related factor 2; PEDF: pigment epithelium-derived factor; PPARγ: peroxisome proliferator-activated receptor gamma; RAGE: receptor of advanced glycated end products; rhFGF-21: recombinant human fibroblast growth factor-21; ROS: reactive oxygen species; SIRT1: sirtuin 1; SOD: superoxide dismutase; TLR: toll-like receptor; TNF-α: tumor necrosis factor alpha.