Diabetes represents a significant global health challenge, affecting approximately 425 million individuals worldwide, with projections indicating a rise in both Type 1 Diabetes (T1D) and Type 2 Diabetes [1]. Despite distinct etiologies, both types are associated with multifarious complications impacting cardiovascular health, kidney function, ocular integrity, and neural health [2], [3]. Among these complications, Diabetic Retinopathy (DR) stands out as a microvascular disorder leading to neurodegenerative processes, often presenting clinically late despite prolonged periods of poorly controlled diabetes [4]. The neurodegenerative cascades characteristic of DR are intertwined with the intricate architecture and cellular composition of the retina [5], typically manifesting clinical signs years after diabetes onset [6].

Inflammation has emerged as a pivotal process underpinning various physiological and molecular alterations observed in the retinas and vitreous humor of diabetic individuals and animals over the past decades [7]. A growing body of evidence highlights inflammation's pivotal role in DR development, emphasizing the potential benefit of its regulation in averting irreversible vascular and neuronal disturbances [8], [9]. A critical pathological hallmark of DR lies in the perturbation of the Blood-Retinal Barrier (BRB), closely associated with inflammatory cascades accompanying DR progression [10]. The integrity of the BRB, when compromised, can be influenced by circulating monocytes, tissue-resident macrophages, or microglial cells, alongside monocyte-derived inflammatory macrophages impacting retinal health [11], exerting diverse regulatory functions within the tissue milieu [12]. Several retinopathy models have demonstrated the migration of circulating macrophages to sites of damage, activating microglia cells, eliciting secretion of inflammatory mediators, and modulating the ensuing inflammatory milieu [13], [14]. Emerging evidence suggests that recruited macrophages may exhibit distinct reactions to neuroinflammation compared to microglia [15], [16]. However, these recruited macrophages may play complementary roles, and their interplay with microglia is poised to shape disease progression.

Retinal microglial cells, specialized immune cells within the retina exhibiting diverse functional phenotypes, promptly respond to inflammatory signals by releasing cytokines, chemokines, neurotrophic factors, and neurotransmitters, thereby exerting cytotoxic, cytoprotective, and scavenger actions contingent upon the tissue milieu [17]. During retinal neuroinflammation, microglia undergoes activation, giving rise to the production of inflammatory mediators in either pro-inflammatory or anti-inflammatory capacities [18], [19]. Pro-inflammatory mediators, including cytokines such as tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL1β), interleukin-6 (IL6), and chemokines such as interleukin-8 (IL8) and C-C Motif Chemokine Ligand 2 (CCL2), potentiate inflammation by orchestrating immune cell recruitment, enhancing vascular permeability, and instigating tissue injury [20], [21]. Conversely, anti-inflammatory mediators, exemplified by cytokines like interleukin-10 (IL10) and transforming growth factor-beta (TGF-β), along with neuroprotective factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), function to dampen inflammation, foster tissue repair, and bolster neuronal viability [13]. Nevertheless, therapeutic interventions targeting the initial inflammatory cascades in DR to impede disease progression and safeguard visual function remain elusive. Notably, investigations employing salicylates, minocycline, and somatostatin in DR patients have furnished evidence supporting the potential of modulating the inflammatory response to forestall enduring vascular and neuronal disruptions [22], [23]. Presently, burgeoning interest revolves around the quest for novel anti-inflammatory agents, given inflammation's pivotal role in DR pathogenesis [24] and other pathologies [25], [26].

Kaempferol (Kae), a naturally occurring flavonoid, has attracted significant attention within the scientific community [27]. Its derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside (K-3-rh)/6-hydroxykaempferol 3, 6-di-O-β-D-glucoside, and kaempferide. Emerging evidence from modern pharmacological research suggests that kaempferol and its derivatives possess neuroprotective properties, particularly in the treatment of neurodegenerative diseases [28]. At the cellular level, kaempferol demonstrates anti-inflammatory effects. In a PC12 cell model subjected to 6-hydroxydopamine (6-OHDA) treatment, kaempferol significantly suppresses the expression of inducible nitric oxide synthase (iNOS) and nuclear factor kappa-B (NF-κB), while enhancing cell viability [29]. Moreover, several signaling pathways have been implicated in the upregulation of HO-1 under various stimuli [30]. For instance, mitogen-activated protein kinases (MAPKs), AMP-activated protein kinases, and nuclear factor erythroid 2-related factor 2 (Nrf2) are suggested to be involved in HO-1 expression induced by kaempferol in PC12 and BV-2 microglia cells [31], [32].

Furthermore, kaempferol-induced HO-1 expression was found to be abolished by pretreatment with inhibitors of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinases (JNK)1/2, reactive oxygen species (ROS), protein kinase C (PKC)α, and NADPH oxidase (NOX) [33]. This subsequently upregulates caspase-3 expression, ultimately mitigating apoptosis in PC12 cells and providing cellular protection [34]. Kaempferol's influence extends to modulating signaling transduction pathways implicated in apoptosis, angiogenesis, inflammation, oxidative stress, and metastasis [35]. Notably, it exerts anti-inflammatory activity by targeting the NF-κB pathway [36], suppressing the mitogen-activated protein kinase (MAPK) signaling pathway [37], and inhibiting NLRP3 inflammasome activation [38]. Additionally, kaempferol has been observed to curb the production of pro-inflammatory cytokines, such as TNFα and IL6, in immune cells (Lin et al., 2019). Its broad spectrum of biological effects, including anti-cancer properties, anti-inflammatory capabilities, and antioxidant activity, underscores its multifaceted therapeutic potential [39], [40]. In the realm of retinal microglial cells, Kaempferol emerges as a promising compound for preempting and addressing the degenerative processes associated with retinal disorders, exemplified by retinitis pigmentosa and age-related macular degeneration [41], Al [42]. Recent studies indicate Kaempferol's protective effect on Retinal Pigment Epithelial (RPE) cells, wherein it modulates various signaling pathways involved in inflammation and apoptotic cell death Al [42]. Moreover, Kaempferol has been demonstrated to enhance the survival and functionality of retinal cells under diverse stress conditions, holding potential implications for delaying or reversing the progression of retinal degenerative diseases [43]. The investigation of Kaempferol's impact on Diabetic Retinopathy (DR) represents an active area of research, poised to unveil novel therapeutic targets and strategies for managing retinal disorders.

The recognition of inflammation and immune responses in DR pathogenesis has prompted a reassessment of its triggers, with novel approaches emphasizing the modulation of inflammation and the immune system. This study highlights Kaempferol's anti-inflammatory effects on DR progression, not only by suppressing the pro-inflammatory response but also by eliciting an anti-inflammatory response primarily mediated by retinal microglia. The interplay between the innate retinal immune system, represented by microglia, and the innate peripheral immune system gaining access through Blood-Retinal Barrier (BRB) permeabilization, significantly influences the retinal pro-inflammatory milieu during DR.