Diabetic nephropathy (DN) is a microvascular complication caused by diabetes-induced glomerular capillary damage. The main pathogenesis comprises glucose metabolism disorder, abnormal renal hemodynamics, extracellular matrix accumulation, abnormal expression of cytokines, genetic factors, and reactive oxygen species (ROS) formation (Wolf, 2004).

Numerous studies have demonstrated that inflammation plays a key role in DN pathogenesis, proving possible regulatory mechanisms (Matoba et al., 2019). NF-κB signal pathway is not only one of the principal inflammatory signal pathways in DN progression but also the signal pathway that governs DNA transcription in vivo. One recent study revealed that long intergenic noncoding RNA (lincRNA)-Gm4419 expression is elevated in mesangial cells (MCs) under a high glucose medium. Gm4419 can directly interact with P50, a functional subunit of NF-κB, activating NF-κB pathway. Meanwhile, P50 promotes transcription of NLRP3 inflammasome and inflammatory cytokines. These results indicate that Gm4419 may contribute to inflammation, fibrosis, and proliferation in MCs exposed to high glucose via NF-κB/NLRP3 inflammasome signaling pathway (Yi et al., 2017). NLRP3 inflammasome activation causes podocyte pyroptosis, proliferation of MCs, and renal tubular injury (Xiong et al., 2021). Interestingly, P50 can form a positive synergistic Gm4419 regulation in MCs (Yi et al., 2017).

Studies have indicated that lncRNAs can act as regulators by interacting with particular miRNAs in DN. Zhang C et al. found that lncRNAs promote podocyte pyroptosis by NLRP3 upregulation through interaction with microRNA (miR)-486a-3p. Additionally, podocytes were induced by sublytic complement C5b-9 (sC5b-9) in vitro (Zhang et al., 2021). This means that lncRNA/miRNA/NLRP3 signal pathway can be activated under specific conditions. Another experiment revealed that DN serum samples and high-glucose (HG)-treated MCs increased lncRNA-HLA complex P5 (HCP5) and high mobility group AT-hook 2 (HMGA2) expression and decreased miR-93-5p expression. Experiments have verified that lncRNA-HCP5 upregulates HMGA2 expression via miR-93-5p sponging. Additionally, HMGA2 can promote the release of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Therefore, targeting lncRNA-HCP5/miR-93-5p/HMGA2 axis can inhibit hyperproliferation, fibrosis, and inflammation of HG-treated MCs (Wang X. et al., 2021). In addition, there are additional similar signaling pathways that have a similar function in DN (Li et al., 2017b; Liu et al., 2020; Zhan et al., 2020; Zhu et al., 2020). Specifically, long noncoding RNA-growth arrest-specific 5 (lncRNA-GAS5) expression was downregulated in HG-induced human renal tubular (HK-2) cells. Meanwhile, GAS5 overexpression could downregulate the expression of NLRP3, cleaved-caspase1, IL-1β, and GSDMD-N by directly targeting miR-452-5p (Xie et al., 2019). However, the specific inhibitory mechanism remains unclear. It may competitively inhibit NLRP3 expression by promoting the expression of specific downstream genes.

Thioredoxin-interacting protein (TXNIP) as a mediator of OS (oxidative stress) was implicated in activating NLRP3 inflammasome in DN progression (Samra et al., 2016). Both lncRNA-antisense noncoding RNA in the INK4 locus (ANRIL) and TXNIP expressions were significantly increased in DN kidney tissues and HG-treated HK-2 cells, whereas miR-497 was reduced. ANRIL has been proved to promote pyroptosis in DN, most likely via miR-497/TXNIP/NLRP3 pathway transmission (Wang and Zhao, 2021). Another research revealed that maternally expressed 3 (MEG3) knockdown resisted hyperoxia-induced lung cell pyroptosis by promoting miR-18a expression, whereas miR-18a inhibited TXNIP (Zou et al., 2020).

Overall, these outcomes reveal that lncRNA plays a critical part in DN pathogenesis (Table 2). In recent years, DN-specific processes, such as podocyte loss, glomerulosclerosis, and tubulointerstitial fibrosis, mediated by lncRNA through acting on NLRP3 inflammasome, have garnered considerable attention. However, the critical regulatory targets remain unknown. Further mechanism research is required to provide new ideas for DN treatment.

Diabetic retinopathy (DR) is a significant consequence of diabetes caused by diabetic microvascular disease. Approximately one-third of diabetic patients have DR (Wong et al., 2016). The pathophysiological processes of DR mainly include abnormal proliferation, migration, and neovascularization in the retina (Cai et al., 2021).

Although the mechanisms by which lncRNAs contribute to DR remain largely unclear, an increasing number of studies has demonstrated critical regulatory functions of various lncRNAs in microvascular dysfunction. For instance, Yan et al. has explored the mechanism of retinal microvascular dysfunction caused by diabetes and found that lncRNA-myocardial infarction-associated transcript (MIAT) expression increased in diabetic retinopathy. MIAT can act as a competing endogenous RNA, forming a feedback loop with vascular endothelial growth factor and miR-150-5p to regulate endothelial cell function, thereby contributing to pathological angiogenesis (Yan et al., 2015).

DR is a major cause of blindness in middle-aged and elderly patients. Visual function is a significant function of the body. If it can be protected early, it improves health-related quality of life in patients. Recently, one research has demonstrated that lncRNA small nucleolar RNA host gene 16 (SNHG16) upregulation in HG-stimulated human retinal microvascular endothelial cells (hRMECs) reduces proliferative DR-related abnormalities in cell proliferation, migration, and angiogenesis via regulating miR-146a-5p/interleukin-1 receptor-associated kinase 1 (IRAK1) and miR-7-5p/insulin receptor substrate 1 (IRS1) to activate NF-κB and phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways (Cai et al., 2021). It was also confirmed that SNHG16 exerts its function by isolating miR-146a-5p and miR-7-5p (Cai et al., 2021). Therefore, SNHG16 can guide individual therapy in DR. Another experiment revealed that in retinal pigment epithelial (ARPE-19) cells with HG conditions, lncRNA H19 and silence information regulator factor-related enzymes 1 (SIRT1) decreased while miR-19b increased. Besides, SIRT1 suppresses the expression of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6 (Luo et al., 2021).

LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) knockdown prevents hyper-proliferation of retinal endothelial cells through p38 mitogen-activated protein kinase (MAPK) signaling (Liu et al., 2014). This year, another research has demonstrated that NLRP3 promoted tube formation and angiogenesis of retinal microvascular endothelial cells (Zou et al., 2021). Also, the findings indicated that NLRP3-mediated aberrant retinal angiogenesis in DR was regulated via apoptosis signal-regulating kinase 1 (ASK1)/p38 axis (Zou et al., 2021). Obviously, MALAT1 regulates diabetes-related retinal vessel function by activating ASK1/p38/NLRP3 signaling pathway.

Diabetic cardiomyopathy (DCM) is a serious end-stage complication related to diabetes. Nowadays, it is recognized that DCM pathogenesis includes hyperglycemia, protein non-enzymatic glycosylation, oxidative stress, myocardial fibrosis, abnormal calcium ion transport, increased fatty acid oxidation, neuroendocrine function activation, etc. (Yilmaz et al., 2015).

Myocardial fibrosis is one of the main causes of DCM. One study revealed that lncRNA-MALAT1 is elevated in diabetic mice and cardiac fibroblasts (CFs) treated with high glucose. Melatonin has the function of reducing collagen production in CFs treated with high glucose. It suppresses lncRNA-MALAT1/miR-141-mediated inflammatory activation of NLRP3 inflammasome and transforming growth factor (TGF)-β1/Smads signaling to produce anti-myocardial fibrosis effects (Che et al., 2020b). Other researchers discovered that lncRNA-Kcnq1ot1 was highly upregulated in diabetic myocardial tissues and CFs cultured under high glucose. After silencing lncRNA-Kcnq1 overlapping transcript 1 (Kcnq1ot1), miR-214-3p can inhibit caspase-1 due to the competitive binding between Kcnq1ot1 and miR-214-3p turns into loosening. Additionally, its downstream inflammatory cytokine IL-1β reduces collagen deposition and myocardial fibrosis (Yang et al., 2018). Therefore, Kcnq1ot1/miR-214-3p/caspase-1 regulatory signaling pathway is critical for regulating DCM myocardial fibrosis.

Inflammation has a key role in DCM development and progression. A study in 2020 revealed that lncRNA-GAS5 expression was upregulated in AC16 cardiomyocytes induced by high glucose. Additional studies indicated that lncRNA-GAS5 could competitively bind to miR-21-5p. Because miR-21-5p targets Toll-like receptor 4 (TLR4), silencing GAS5 can partially inhibit miR-21-5p-mediated TLR4/NF-κB signaling pathway, hence reducing inflammatory response triggered by high glucose (Zhao et al., 2020). However, another study concluded the opposite result. Xu, Y. et al. induced cardiac muscle cell line (HL-1) cardiomyocytes by high glucose and found that GAS5 was severely downregulated in DCM mice. Further experiments revealed that GAS5 overexpression could inhibit NLRP3 activation by regulating miR-34b-3p/aryl hydrocarbon receptor (AHR) signaling pathway, thereby reducing cardiomyocytes pyroptosis (Xu et al., 2020). The different results may be due to differences between cell lines or because multiple regulatory pathways coexist in the cell. As DCM is a complication of diabetes, the principal Frontier of its research is self-evident. To summarize, these results imply that lncRNA might be an underlying therapeutic target for DCM by alleviating NLRP3 inflammasome activation, fibrosis, and apoptosis.

Diabetic peripheral neuropathy (DPN) is a ubiquitous complication of diabetes. Redox-sensitive transcription factors such as NF-кB play a critical role in triggering the cascade of cytokine and chemokine production, including proinflammatory cytokines IL-1β, IL-6, TNF-α, etc. (Zhou and Zhou, 2014). These are key inflammatory factors downstream of NLRP3 inflammasome and are involved in inflammatory response of DPN, which can not only enhance inflammation and immune response but also promote activation of various downstream cell oxidative stress pathways. Wang, C. et al. employed whole-transcriptome sequencing technology to systematically analyze the differential expression of lncRNAs, mRNAs, and miRNAs in Schwann cells (SCs) of DPN and control rats and constructed lncRNA–miRNA–mRNA competing endogenous RNA (ceRNA) network of SCs. This network has identified the inhibited relationship of lncRNA, miRNA, and mRNA and underlined that they function as key mediators in the pathophysiological process of SCs in DPN (Wang et al., 2020). This ceRNA regulatory network has a particular clinical application value in DPN. Another recent array study demonstrated that four lncRNAs, namely XR_353891, XR_600244, XR_595664, and XR_598132, can regulate inflammation signaling pathways by competitively binding with miR-146a-5p in DPN rats using qRT-PCR (Feng et al., 2020). LncRNA HLA complex group 18 (HCG18) promotes the polarization of M1 macrophages and DPN progression by regulating miR-146a/TNF receptor-associated factor 6 (TRAF6) axis. Additionally, in DPN model, inflammatory factors, such as TNF-α, IL-1β, and IL-6, are upregulated (Ren et al., 2021).

Diabetic foot is a serious complication of diabetes, mainly caused by DPN, peripheral vascular diseases, or infection. As known, lncRNAs usually act as sponges for microRNAs to exert their regulatory effects. However, some ceRNAs in diabetic feet require additional investigation. For instance, inhibiting miR-217 can upregulate hypoxia-inducible factor-1 (HIF-1α)/vascular endothelial growth factor (VEGF) pathway to promote angiogenesis in diabetic foot ulcer rats and effectively improve inflammatory response by decreasing inflammatory factors (IL-1β, TNF-α, and IL-6) (Lin et al., 2019). Furthermore, emodin has been demonstrated to protect diabetic foot through miR-9 upregulation and modulation of PI3K/AKT and NF-κB signaling pathways in neuron-like PC-12 cells (Fan et al., 2018). Consequently, it is imperative to further investigate the interaction and contrast relationship between lncRNA and miRNA to better cure diabetic foot.

The incidence of diabetic osteoarthritis (OA) increases, making it critical to identify an exact therapy. One research has verified that lncRNA plasmacytoma variant translocation 1 (PVT1) promoted cartilage degradation in diabetic OA mice by downregulating miR-146a and activating TGF-β/mothers against decapentaplegic homolog 4 (SMAD4) signaling pathway. It has been demonstrated that silencing PVT1 decreases the expression of proinflammatory mediators such as TNF-α, IL-1, IL-6, and TGF-β1, hence alleviating joint inflammation (Wang Y.-Z. et al., 2021). Interestingly, another experiment confirmed that PVT1 silencing could act as a sponge for miR-149 to combat metabolic imbalance to catabolism and inflammation after IL-1β exposure (Zhao et al., 2018). It provided a new direction for diabetic OA treatment.

Melatonin can be produced by the pineal gland and is also present in various plants. It possesses pharmacological activities, including antioxidant, anti-inflammatory, liver protection, heart protection, and neuroprotection properties. In recent years, the effect of treating cancer and diabetes has been demonstrated (Ashrafizadeh et al., 2021). The clinical use of melatonin is controversial (Garaulet et al., 2020), but there are now some basic studies on its mechanism for different diabetes complications. For instance, melatonin has been demonstrated to have a protective effect of alleviating cardiac fibrosis on DCM by inhibiting lncRNA MALAT1. miR-141-5p, which acts as a sponge of MALAT1, inhibits the expression of NLRP3 inflammasome and TGF-β1/Smads signaling (Table 3) (Che et al., 2020c). TGF-β1 can initiate cardiac fibrosis via regulating extracellular matrix proteins in cardiac fibroblasts through activating Smads-mediated signal pathways in diabetic mice (Chen et al., 2015). In another work, melatonin can inhibit OS and inflammation by enhancing the activity of long non-coding RNA MEG3/miR-204/Sirt1 axis in experimental DR rats (Tu et al., 2020). Sirt1 can deacetylate the target gene forkhead box o1 (Foxo1) and the subunit p65 of NF-κB, leading to downregulation of inflammatory factors (Tu et al., 2021). Therefore, melatonin may be implemented as a potential agent for treating diabetic neuropathy (Che et al., 2020a).

Metformin has become a ‘foundation therapy’ for treating diabetes due to its excellent efficacy and safety. As a first-line treatment option for diabetes, metformin effectively controls the amount of glycogen when used alone or in combination with other drugs, such as sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, and GLP-1 receptor agonist or insulin (Sanchez-Rangel and Inzucchi, 2017). Recently, metformin has been confirmed to regulate lncRNA-mediated NLRP3 inflammasome in diabetes complications. Diabetic periodontitis is caused by diabetes leading to excessive inflammatory response of periodontal microbiome, and it subsequently increases insulin resistance (Lalla and Papapanou, 2011). NIMA-related kinases 7 (NEK7) is an essential mediator of NLRP3 activation downstream of potassium efflux (He et al., 2016). One research has revealed that metformin suppresses NEK7 expression in diabetic periodontitis to improve NLPP3 inflammasome-mediated pyroptosis (Zhou et al., 2020). Therefore, with additional research into the mechanism of action, metformin has a good clinical treatment prospect in diabetes and its complications, which warrants much attention.

Atorvastatin (AT) has lipid-decreasing, anticoagulant, antioxidative and anti-inflammatory functions (Shi M.-M. et al., 2016). Clinically, AT is often universally applied to treat lipid abnormalities and related angiopathies. Nuclear factor erythroid-2-related factor 2 (NRF2) plays a tremendous role in regulating OS and is lowly expressed under HG environments (Uruno et al., 2015). For example, one study has indicated that NRF2 hyperactivation can induce nephrogenic diabetes insipidus in early renal tube development (Suzuki et al., 2017). LncRNA MALAT1 is thought to be intimately linked to pyroptosis in diabetes complications (Li et al., 2017a). Interestingly, MALAT1 can stabilize and activate NRF2 in human umbilical vein endothelial cells under H₂O₂ disposed (Zeng et al., 2018). miR-200c overexpression can promote OS in endothelial cells and interact with MALAT1 structurally (Li et al., 2016; Carlomosti et al., 2017). In addition, Zuo Y et al. demonstrated that AT suppresses caspase-1, GSDMD, and NLRP3 expressions by regulating MALAT1/miR-200c/NRF2 activation to prevent podocyte pyrolysis and OS induced by high glucose (Zuo et al., 2021). It opens a new door to AT-induced therapy for diabetes complications.

Sinapic acid, a small naturally occurring hydroxycinnamic acid, contains 3,5-dimethoxyl and 4-hydroxyl substitutions in the phenyl ring of cinnamic acid. Sinapic acid is well known to show antioxidant, anti-inflammatory, anticancer, antiglycemic, and neuroprotective activities (Chen, 2016). Numerous regulation mechanisms for sinapic acid in diabetes and its complications have been revealed (Zych et al., 2019; Alaofi, 2020; Altındağ et al., 2021). Diabetic atherosclerosis is caused by chronic inflammation, dyslipidemia, and vascular endothelial injury under high blood sugar levels and is also an important cause of death and disability in diabetic patients (Giacco and Brownlee, 2010). It was stated that sinapic acid could alleviate inflammatory responses via inhibiting NLRP3 inflammasome activation (Lee et al., 2021). Recently, a study revealed that low-dose sinapic acid inhibits lncRNA-MALAT1 to downregulate NLRP3 expression, thereby alleviating macrophage pyroptosis in diabetic atherosclerosis rats (Han et al., 2018). These outcomes have revealed that sinapic acid has potential therapeutic value for diabetes complications.

In short, NLRP3 inflammasome is required for the inflammatory signaling pathway. IL-1β, IL-18, caspase-1, caspase-11, and NF-κB are important inflammatory factors in the inflammatory signaling pathway, whose expression indicates the role of NLRP3 inflammasome (Al Mamun et al., 2021). Simultaneously, the function of NLRP3 inflammasome provides a vital theoretical basis for using lncRNA as a therapeutic target to treat diabetes complications.