LncRNA NEAT1 in skin disorders: Pathophysiological insights and emerging therapeutic strategies

Abstract

Long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) is a critical component of nuclear paraspeckles, influencing gene expression through epigenetic, transcriptional, and post-transcriptional mechanisms. The dysregulated expression and function of NEAT1 are associated with diverse human disorders ranging from inflammatory diseases to cancers. However, the emerging pathophysiological roles and therapeutic strategies of NEAT1 in skin disorders have not yet been thoroughly reviewed and discussed. This review offers a comprehensive perspective and discusses the recent therapy progress on NEAT1 in skin disorders, mainly, including skin cancers and immune-related conditions. NEAT1 is always upregulated in various skin disorders, such as systemic lupus erythematosus (SLE), atopic dermatitis (AD), and melanoma, which primarily functions as a competitive endogenous RNA (ceRNA) via targeting microRNA and regulates multiple immune cells to exert pathogenic effects. Notably, the expression levels of NEAT1 in psoriasis studies present contrary results, with some studies showing increased expression and others indicating downregulation, making its role in the pathophysiology of psoriasis appear complex, and its specific regulation of different cells requires further research. Moreover, technologies focusing on NEAT1 inhibition with upstream element regulation and direct silencing, and NEAT1 overexpression based on drug induction and exogenous introduction, are growing vigorously. In conclusion, this review provides significant insights into potential diagnostic biomarkers and therapeutic targets of NEAT1 for these disorders.

Introduction

Long non-coding RNAs (lncRNAs), defined as non-coding RNAs longer than 200 nucleotides, regulate cellular functions through transcriptional, post-transcriptional, and epigenetic mechanisms, depending on their subcellular localization.^[1–3] LncRNAs play crucial roles in immunological responses, substance metabolism, development and growth, and other biological processes.^[4] Increasing evidence implicates the dysregulation of some crucial lncRNAs as being inherently involved in various diseases, including skin disorders.^[5] Recent studies have profiled lncRNA expression in skin cells, laying the groundwork for understanding their roles in skin homeostasis and disease pathogenesis.^[6] Functional studies have demonstrated that lncRNAs influence keratinocyte (KC) differentiation, epidermal homeostasis, neoplastic progression, and the development of inflammatory skin disorders.^[7]

Despite their importance, lncRNAs are typically characterized by low abundance and cell-specific expression, complicating efforts to elucidate their functions. Even within the same tissue, the expression levels of lncRNAs vary across regions, developmental stages, and environmental factors.^[1,8] Among these, nuclear enriched abundant transcript 1 (NEAT1) stands out as an abundant structural lncRNA in various tissues, including skin.^[5,9] Additionally, a few lncRNAs are expressed across different cell types in skin, including NEAT1.^[10] NEAT1 is typically upregulated during cellular stress responses and specific developmental phases.^[11–13] It regulates gene expression through mechanisms, such as paraspeckle formation, acting as a competitive endogenous RNA (ceRNA), and epigenetic modifications. NEAT1 participates in diverse physiological and pathological processes, including cell proliferation, cell differentiation, cell death,^[14–16] organ development,^[17] and immune responses.^[18] The abnormal expression of NEAT1 exhibits both protective and harmful effects depending on the context, underscoring its potential as a diagnostic biomarker and therapeutic target.^[19,20] Current research has primarily focused on its roles in the digestive, respiratory, nervous, and genitourinary systems and related diseases, while its functions in skin disorders remain underexplored.^[21]

This review synthesizes recent findings on NEAT1 expression and its roles in skin disorders, emphasizing its association with imbalances in skin homeostasis. We propose that NEAT1 is crucial for maintaining normal skin function and is a pivotal factor in the onset and progression of skin diseases. This work aims to advance understanding of NEAT1-related pathogenesis, targeted therapies, and prognostic approaches in skin disorders.

NEAT1 Overview

Structures of NEAT1 and paraspeckles

NEAT1 is a polyadenylated non-coding RNA transcribed by polymerase II from the human chromosome 11q13.1.^[22] It has two overlapping isoforms, NEAT1_1 (3.7 kb) and NEAT1_2 (22.7 kb), localized to paraspeckles. NEAT1_1 can keep the transcriptional locus active and rapidly switch to NEAT1_2 during stress response.^[23,24] Paraspeckles, mammal-specific subnuclear ribonucleoprotein structures found in most cultured cells, are organized with NEAT1_2’s central domain forming the core, while NEAT1_1 and the terminal regions of NEAT1_2 reside at the periphery. NEAT1 functions as a scaffold for paraspeckle proteins, such as paraspeckle component 1, 54 kDa RNA binding protein/non-POU domain-containing octamer-binding protein (p54^nrb/NONO), and polypyrimidine tract binding protein-associated splicing factor, enabling their structured assembly into spheroidal configurations [Figure 1].^[25] Notably, NEAT1_2 is indispensable for paraspeckle formation and stability, while the role of NEAT1_1 in paraspeckle architecture remains unclear. Recent studies suggest that NEAT1_1 may translocate to the cytoplasm, performing paraspeckle-independent functions.^[26–28]

Figure 1.

Structural features of NEAT1 and paraspeckles. The NEAT1 gene, located on chromosome 11q13.1, encodes two isoforms distinguished by their 3′-ends: NEAT1_1, which terminates with a polyadenine tail, and NEAT1_2, characterized by a unique three-helix structure. NEAT1_2 possesses three essential domains for binding with paraspeckle-associated proteins, such as p54^nrb/NONO (yellow), PSPC1 (green), and PSF/SFPQ (blue). The proteins can form heterodimers in various combinations. The central domain of NEAT1_2 (pink) forms the paraspeckle core, while NEAT1_1 and the terminal ends of NEAT1_2 (orange) are positioned at the periphery. NEAT1: Nuclear-enriched abundant transcript 1; PSPC1: Paraspeckle component 1; p54^nrb/NONO: 54 kDa RNA binding protein/Non-POU domain-containing octamer-binding protein; PSF/SFPQ: Polypyrimidine tract-binding protein (PTB)-associated splicing factor/Splicing factor proline- and glutamine-rich. Created with BioRender.com.

Cellular functions and specific mechanisms of NEAT1

NEAT1 and paraspeckles are usually upregulated in response to cellular stress.^[29] Multiple studies have elucidated molecular mechanisms governing NEAT1 expression, identifying key regulatory factors. Primary modulators of NEAT1 expression—operating at both transcriptional and post-transcriptional levels—include stress-induced transcription factors (e.g., hypoxia-inducible factor 2 alpha (HIF-2α), heat shock factor 1, tumor protein p53, activating transcription factor 2, nuclear factor-kappa B) and RNA-binding proteins (e.g., TAR DNA-binding protein 43, heterogeneous nuclear ribonucleoprotein M , AU-rich binding factor 1, human antigen R, Lin28 homolog B, serine and arginine rich splicing factor 1). These molecules can modify NEAT1 gene transcriptional activity, stabilize NEAT1, and alter RNA shearing.^[23,30] NEAT1 primarily regulates gene expression through paraspeckle-dependent and independent mechanisms [Figure 2].^[31] Paraspeckles influence gene regulation via adenosine-to-inosine (A-to-I) RNA editing and nuclear retention, processes linked to inflammation and tumor development. A-to-I editing is a common genetic information modification mechanism that facilitates the conversion of adenosine to inosine at specific sites in the primary messenger RNA (pri-mRNAs). This process is catalyzed by adenosine deaminase acting on RNA (ADAR), mostly occurring in inverted repeated Alu elements (IRAlus). Modified mRNAs bind paraspeckle proteins, retaining transcripts in the nucleus and inhibiting translation.^[32] NEAT1 also impacts mitochondrial dynamics by regulating mito-mRNA sequestration in paraspeckles, highlighting its potential role in organelle interactions.^[33,34] Additionally, paraspeckle protein components like paraspeckle component 1 (PSPC1), polypyrimidine tract-binding protein (PTB)-associated splicing factor/splicing factor proline- and glutamine-rich (PSF/SFPQ), and p54^nrb/NONO, proteins of the drosophila behavior and human splicing (DBHS) family, mediate transcriptional processes, such as repression, activation, initiation, elongation, and termination.^[35] During the formation of nuclear paraspeckles, NEAT1 binding affects these proteins’ interactions with gene promoters, modulating transcriptional regulation.^[36] Furthermore, NEAT1 supports primary microRNA (pri-miRNA) biogenesis and maturation by scaffolding DiGeorge syndrome chromosomal region 8 (DGCR8), a microprocessor complex subunit essential for primary microRNA (pri-miRNA) processing, linking paraspeckles to miRNA production.^[37]

Figure 2.

Regulatory roles of NEAT1 in gene expression. The expression of NEAT1 is upregulated under cellular stress. NEAT1, an essential component of nuclear paraspeckles, can regulate gene expression at different levels by participating in paraspeckle formation and other mechanisms.^[9,31] (A) A-to-I edited mRNAs are retained in the nucleus, preventing cytoplasmic transport. (B) NEAT1-dependent paraspeckle formation isolates paraspeckle proteins, limiting transcriptional regulation. (C) NEAT1 acts as a scaffold for RNA-binding proteins and the microprocessor, enhancing pri-miRNA processing. (D) NEAT1 functions as a ceRNA, sequestering miRNAs and increasing mRNA expression. (E) NEAT1 regulates DNA and histone modifications, including acetylation and methylation. A to-I editing: Adenosine-to-inosine editing; pre-miRNA: Precursor microRNA; pri-miRNA: Primary microRNA; NEAT1: Nuclear-enriched abundant transcript 1. Created with BioRender.com.

Besides contributing to the formation of paraspeckles, NEAT1 can also regulate gene expression through other mechanisms. Multiple studies have validated the competing endogenous RNA (ceRNA) hypothesis, demonstrating NEAT1’s role as a miRNA sponge. By sequestering miRNAs, NEAT1 reduces their regulatory effects on target mRNAs, activating downstream protein expression. The ceRNA network, formed by diverse NEAT1/miRNA/target axes, plays a significant role in oncogenesis and other processes.^[38] Furthermore, NEAT1 participates in gene epigenetic regulation through DNA and histone modifications. For instance, it promotes DNA methylation of the CpG island in the miR-129 gene, silencing miR-129 expression.^[39] It also inhibits the expression of smooth muscle (SM)-specific genes by reducing the enrichment of active histone modifications (H3K4me3 and H3K9ac) and increasing the abundance of inactive ones (H3K27me3) at the promoters of these genes.^[40,41]

Roles of NEAT1 in Skin Diseases and Potential Therapeutic Strategies

Skin tumors

In skin tumors, lncRNA affects cell proliferation, migration, extracellular stromal remodeling, and epithelial-mesenchymal transition (EMT) by regulating proto-oncogene/cancer suppressor genes, proliferation/apoptosis signaling pathways, cyclin, protease, and other molecules. It also contributes to the progression of various dermatological diseases. A pan-cancer analysis identified NEAT1 as a lncRNA with the highest number of cancer gene targets.^[42] Its elevated expression level is linked to treatment resistance and worse clinical outcomes. NEAT1 mainly acts as a ceRNA to turn the tumor-suppressive miRNA into a sponge, allowing the translation of oncogenic mRNAs and triggering tumorigenesis.^[38,43] Adriaens et al reported that NEAT1 and paraspeckles, typically undetectable in healthy mouse skin, are overexpressed in malignant and borderline lesions. NEAT1 knockout and heterozygous mice exhibit smaller papillomas and lower rates of malignant squamous cell carcinoma development compared to wild-type mice. Hence, NEAT1 may promote skin tumorigenesis.^[44]

Hemangioma (HA)

HA is one of the most prevalent benign vascular tumors in infancy, affecting ~5% of mature neonates. Most cases regress spontaneously, but 10–15% may result in severe complications, such as vision impairment, ulceration, and disfigurement.^[45] Abnormal proliferation of endothelial cells contributes to HA development, but its pathogenesis is unclear.

NEAT1 is overexpressed in HA tissues, and its silencing can inhibit HA tumorigenesis. Therefore, NEAT1 is a risk factor for HA. According to Yu et al,^[46,47] NEAT1 stimulates the nuclear factor-kappa B signaling pathway via NEAT1/miR-33a-5p/hypoxia-inducible factor-1 alpha axis, inducing proliferation, migration, and invasion of HA endothelial cells (HemEC). Another study demonstrated that the NEAT1/miR-361-5p/vascular endothelial growth factor A axis inhibits HemEC apoptosis and promotes HA progression.^[48,49] The expression of alkylation repair homolog protein 5 (ALKBH5) was increased in HA tissues, associated with carcinogenesis by reducing m6A modification of NEAT1 and upregulating the expression level of NEAT1 [Figure 3A].^[50] Overexpressed NEAT1 promotes HA cell tumor-like behavior by adsorbing miR-378b and targeting FOS-like antigen 1.^[51] NEAT1 can be suppressed via small interfering RNA targeting NEAT1^[46] or short hairpin RNA targeting NEAT1,^[48] or targeting m6A erasers of NEAT1 [Figure 3B].^[51] Hence, NEAT1 can be a potential therapeutic strategy for HA.

Figure 3.

Therapeutic strategies targeting NEAT1 in preclinical skin disorder studies. (A and B) NEAT1 plays a negative role in most skin diseases. Thus, strategies to downregulate NEAT1 are a promising therapeutic approach. (A) Using shRNA of ALKKBH5 (sh-ALKBH5), an upstream regulator of NEAT1, to silence the NEAT1/miR-378b/FOSL1 axis can suppress HA.^[51] (B) Most studies summarized in this review employed the transduction of si-NEAT1 or sh-NEAT1 plasmid to silence NEAT1. CRISPR was also used to knock down the NEAT1 gene in mice.^[72] (C and D) Positive functions of NEAT1 have been reported across some skin diseases. Several strategies have been developed to elevate the NEAT1 levels in specific types of cells. (C) Paeoniflorin is a feasible drug for psoriasis, which suppresses the proliferation and migration of KCs by enhancing NEAT1 expression.^[82] (D) The autophagy pathway of mouse KCs can be induced by NEAT1, suggesting that ADSC-exo-derived NEAT1 could be a potential therapeutic target to promote wound healing.^[101] ADSC-exo: Adipose-derived mesenchymal stem cell-derived exosome; ALKKBH5: Alkylation repair homolog protein 5; CRISPR: Clustered regularly interspaced shortpalindromic repeats; KCs: Keratinocytes; NEAT1: Nuclear-enriched abundant transcript 1; RISC: RNA-induced silencing complex; si-NEAT1: Small interfering RNA targeting NEAT1; sh-NEAT1: Short hairpin RNA targeting NEAT1. Created with BioRender.com.

Melanoma

Melanoma is an aggressive skin cancer with the highest mortality rate among skin malignancies.^[52] As there is an urgent need to develop early detection markers and novel therapeutic options for metastatic melanoma, it has become the most extensively researched skin disease in lncRNA research. NEAT1 is upregulated in melanoma cells and facilitates proliferation, invasion, and chemotherapy resistance (polyphyllin B and cisplatin).^[53–55] It operates through various pathways, including NEAT1/miR-495-3p/E2F transcription factor 3,^[56] NEAT1/miR-200b-3p/SMAD family member 2,^[57] NEAT1/miR-23a-3p/Krüppel-like factor 3 (KLF3),^[58] and NEAT1/miR-519c-3p/methyl CpG binding protein 2^[59] axes. M2 macrophages promote the growth and spread of melanoma cells and suppress their apoptosis.^[60] Macrophages can ingest NEAT1 in extracellular vesicles from bone marrow mesenchymal stem cells (BMSCs). This process facilitates macrophage M2 polarization via the NEAT1/miR-374a-5p/leucine-rich repeat-containing G protein-coupled receptor 4/IQ motif-containing GTPase-activating protein 1 axis.^[61] It is worth noting that an anti-tumor drug, ganoderic acid, downregulates NEAT1 expression in melanoma cells, inducing ferroptosis and autophagy through the SLC7A11/GPX4 and AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin complex (mTOR) pathways, respectively.^[62] Silencing NEAT1 could serve as an effective therapeutic strategy for melanoma.

Cutaneous squamous cell carcinoma (CSCC)

CSCC, originating from KCs, is the second most common non-melanoma skin cancer. CSCC lacks typical early symptoms, leading to late diagnoses and limited treatment options once the disease has progressed to an aggressive stage.^[63] NEAT1 is overexpressed in CSCC tissues (two-fold higher than paracancer tissues) and is associated with tumor-nodes-metastasis grade and lymph node metastasis. Studies have shown that NEAT1 knockdown inhibits CSCC cell proliferation, invasion, and metastasis in vivo and in vitro.^[64] Mechanistically, NEAT1 promotes CSCC progression by sponging miR-361-5p, upregulating matrix metallopeptidase 1, and activating the WNT pathway.^[65] According to Gong et al,^[66,67] NEAT1 downregulates miR-342-3p to enhance cullin 4B expression, which activates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B signaling pathway, a critical driver of CSCC development. These findings position NEAT1 as a potential biomarker and therapeutic target for CSCC diagnosis and treatment.

Immune-related skin diseases

Immune disorders, with their rising prevalence and poor prognosis, often go undetected in the early stages. Many patients are severely ill by the time they are diagnosed, emphasizing the need for early biomarkers. LncRNAs, including NEAT1, have emerged as significant modulators of immune responses and cancer immunotherapy. The role of NEAT1 in immune responses was first recorded in mice infected with the rabies or Japanese encephalitis viruses. Subsequent research has expanded its involvement in the activation and differentiation of macrophages, T cells, and inflammasomes.^[68] NEAT1 is abnormally expressed in various immune-related diseases, where it influences immune responses by retaining nuclear speckles, sequestering paraspeckle proteins, and acting as a miRNA sponge. Multiple studies have validated the diagnostic utility of NEAT1 in diseases like rheumatoid arthritis and sepsis due to its broad prevalence in clinical samples and high stability in body fluids, including serum, plasma, urine, and saliva. Recent therapeutic approaches have shown NEAT1 can be effectively targeted, underscoring its potential as a candidate for immune-related disease therapies in vivo.^[69,70]

Systemic lupus erythematosus (SLE)

SLE, a typical autoimmune disorder, is characterized by chronic inflammation, high autoantibody levels and low complement protein levels.^[71] Its manifestations can occur throughout the body, causing damage to organs, including the skin, brain, heart, kidneys, and lungs. While no cure exists, early diagnosis and treatment are essential for managing the disease. It is generally believed that the onset of SLE is often accompanied by excessive activation of immune cells. NEAT1 promotes the activation of toll-like receptor 4, toll-like receptor 7, and type I interferon (IFN-I) pathways in granulocytic myeloid-derived suppressor cells, enhancing the B cell IFN-I signaling pathway. The deficiency of NEAT1 disrupts the expression of IFN-I-inducible genes (e.g., Ifit1, Ifit2, Mx1, and Ifi44) in B cells, suggesting a direct regulatory role.^[72] Overexpression of NEAT1 in monocyte-derived dendritic cells (moDCs) drives inflammation via the NEAT1/miR-365a-3p/interleukin (IL)-6 axis, with elevated IL-6 levels correlating positively with SLE progression.^[73] Additionally, NEAT1 contributes to immune cell imbalances in SLE. It is overexpressed in peripheral blood mononuclear cells of SLE patients, disrupting the T helper cell 1/ T helper cell 2 balance, reducing IFN-γ secretion, and increasing IL-4 levels.^[74] Huang et al^[75] noted that NEAT1 enhances the high expression of signal transducer and activator of transcription 6 by suppressing its ubiquitination and degradation. Signal transducer and activator of transcription 6 upregulates GATA3, promoting Th2 cell activation.

Beyond the activation or imbalance of immune cells, the production of cytokines and chemokines is essential for SLE onset. Zhang et al^[76] revealed that NEAT1 is upregulated by lipopolysaccharide via p38 activation, inducing IL-6, C-X-C motif chemokine ligand 10, etc. In addition, NEAT1 affects the activation of MAPK pathway and participates in TLR4-mediated inflammatory process. Notably, after forming nuclear paraspeckles, NEAT1 can translocate splicing factor proline- and glutamine-rich, a vital paraspeckle protein, from the IL-8 promoter to the paraspeckle, activating IL-8 and causing inflammation.^[77] The prior studies suggest that targeting NEAT1 can regulate immune cells and cytokines, inhibiting the progression of SLE.

Psoriasis

Psoriasis is a chronic, T-cell-mediated inflammatory skin disorder characterized by epidermal hyperplasia, KCs hyperproliferation and abnormal differentiation, and hyperplasia of blood vessels. It often coexists with systemic inflammatory responses, such as metabolic, vascular, and nervous system disorders, increasing the risk of cardiovascular and chronic obstructive pulmonary diseases.^[78] Recent studies reveal a significant link between psoriasis and the dysregulated expression of lncRNAs.^[79,80] Fierro et al^[81] proposed a model for NEAT1’s involvement in the correct differentiation process of KCs, and they revealed that NEAT1 enables the recruitment of essential epidermal transcription factors to the promoters of differentiation genes, thus activating the differentiation process. Furthermore, they observed that the expression of NEAT1_2 is reduced in psoriasis lesional skin based on analyzing the Gene Expression Omnibus database (GSE13355) from 58 psoriatic lesional skin and 64 non-lesional skin samples. This reduction likely reflects the proliferation/differentiation imbalance characteristic of psoriasis.^[81] Similarly, another study demonstrated that NEAT1 expression is downregulated in skin samples from 20 psoriasis patients compared to those from 20 healthy controls by quantitative real-time polymerase chain reaction.^[82] In addition, they found that paeoniflorin could increase the expression of NEAT1, which further sponges miR-3194-5p and then upregulates the downstream target Galectin-7, to inhibit the proliferation and migration of psoriatic immortalized human KCs (HaCaT cells) [Figure 3C].^[82] Collectively, these studies indicate that NEAT1 may exert a protective role in the development of psoriasis by promoting the correct differentiation program of KCs and functioning as a ceRNA.

However, Shefler et al^[10] reported that NEAT1 expression is 1.44-fold higher in the lesional skin of psoriasis patients compared to controls without skin disease (false discovery rate ≤0.05). Analysis of the expression profiles in single-cell RNA sequencing data from non-lesional and lesional skin revealed that, contrary to the typical cell type-specific expression patterns of lncRNAs, the highly expressed lncRNA NEAT1 is ubiquitously present across all skin cell types, while the definitive role of NEAT1 in psoriasis is still unknown. Additionally, another study illustrated that NEAT1 was highly expressed in psoriasis-affected areas compared to normal tissue in 204 patients examined by quantitative polymerase chain reaction, and the level of NEAT1 was positively correlated with disease activity, as well as the mRNA level of inflammatory factors, including tumour necrosis factor-alpha (TNF-α), IL-6, IL-8, IL-17, and IL-22.^[83] Moreover, Mostafa et al reported that compared with healthy controls, NEAT1 expression was upregulated in blood samples of psoriasis patients (P <0.001), and its expression levels positively correlated with dyslipidemia, a prevalent comorbidity in psoriasis. They further tested the diagnostic performance of NEAT via receiver operating characteristic analysis and found that the elevated NEAT1 level in blood (0.931 area under curve, 90% specificity, 82% sensitivity) can be a potential biomarker for psoriasis.^[84] However, the specific form and definitive mechanism of NEAT1 still await exploration.

Overall, the controversial results regarding the RNA levels of NEAT1 may be influenced by various factors, including small sample sizes, differences in control types, and the absence of functional mechanism investigations. Additionally, NEAT1 likely presents a dual regulatory role in psoriasis. On the one hand, NEAT1 may act as a protective regulator of the correct differentiation program.^[81] On the other hand, NEAT1 may also exert negative effects in inflammatory responses, such as assembling paraspeckles in the autologous immune cells of the dermis and then stimulating the secretion of inflammatory factors, or directly participating in the immune regulation.^[85,86] Future research needs to further elucidate the cell-specific functions of NEAT1 to achieve targeted therapies for psoriasis.

Atopic dermatitis (AD)

AD is a chronic, relapsing inflammatory skin disease related to the immune system. It not only damages the skin, but also exacerbates asthma and allergic rhinitis. In addition, AD raises the likelihood of developing cataracts, infections, and hypoalbuminemia.^[87,88] While its precise pathogenesis remains unclear, immune dysregulation has been implicated.^[89,90] Previous research has shown that numerous lncRNAs have aberrant expression in AD, driving the inflammatory signaling pathways (especially IL-36, which induces IL-17 and IL-23 pathways). These result in abnormal filaggrin gene expression (FLG and FLG2), weakening the skin barrier and promoting AD onset.^[10] Wang et al^[91] proposed that the lncRNA/miRNA/mRNA network is critical for the progression of several skin disorders, including AD. Peng et al^[92] found that NEAT1 is significantly increased in AD patients’ serum, operating as a core lncRNA of the ceRNA network, including S100 calcium binding protein A9/hsa-miR-588/NEAT1, S100A9/hsa-miR-588/NEAT1, and late cornified envelope 3D (LCE3D)/hsa-miR-1224-5p/NEAT1. However, the specific regulatory mechanisms require further verification.

Rosacea

Rosacea is a chronic, recurrent, inflammatory skin disorder affecting the central face, marked by flushing, erythema, telangiectasia, papules, pustules, and edema. While its pathogenesis remains incompletely understood, it likely involves genetic factors, neurovascular dysregulation, immune dysfunction, microorganisms, and environmental triggers.^[93] Wang et al^[94] re-annotated and analyzed data obtained from the gene expression omnibus database (GSE65914) and reported an overexpression of NEAT1 in rosacea lesions. Moreover, they established a NEAT1/miRNA/mRNA network and identified specific miRNAs (hsa-miR-148b-3p, hsa-miR-148a-3p, hsa-miR-296-3p, hsa-miR-378g, and hsa-miR-152-3p). These miRNAs are strongly linked to the upregulation of certain mRNAs (e.g., CCL19, IL21R, WNT2B, STAT3, ICAM1, and GLUL) and the downregulation of others (e.g., IL20RB, KLF4, and SH3PXD2A) in the network. NEAT1 stimulates rosacea by regulating genes associated with immune dysfunction and inflammatory factors. According to the results of high-throughput RNA sequencing (RNA-seq) and bioinformatics analysis, NEAT1 is upregulated (more than two-fold higher compared to non-lesioned skin) and may enhance the secretion of inflammatory cytokines (e.g., IL-1β, IL-6, oncostatin-M, and TNF-α) via the NEAT1/miR-196a-5p/S100A9 axis. This hypothesis was verified in vitro using LL37-treated HaCaT cells, suggesting that the NEAT1/miR-196a-5p/S100A9 axis could be a novel target for rosacea treatment.^[95]

Others

Non-healing wounds and scar formation

Wound healing is a multi-stage tissue-regeneration process encompassing hemostasis, inflammation, proliferation, and remodeling.^[96] Disruptions in these stages can result in chronic non-healing wounds or excessive repair characterized by hyperplastic scar tissue (HS) or keloids (KDs).^[97] NEAT1 has emerged as a therapeutic target for promoting re-epithelialization in non-healing wounds. Overexpression of NEAT1 in transforming growth factor-beta1 (TGF-β1)-treated HaCaT cells enhances KC proliferation and migration via the NEAT1/miR-26a-5p/leucine-rich repeat-containing G protein-coupled receptor 4 axis.^[98] Additionally, stem cell exosome-derived NEAT1 supports cell autophagy by sponging miR-17-5p and inducing the autophagy protein UNC-51-like kinase 1.^[99]

However, during the remodeling stage, NEAT1-induced fibroblast activity can lead to excessive dermal fibrosis and disorganized collagen deposition, contributing to HS and KD formation [Figure 3D].^[100,101] NEAT1 is overexpressed in KDs, and silencing it inhibits KD fibroblast proliferation and extracellular matrix (ECM) production. Mechanistically, NEAT1 promotes KD formation via pathways, such as the miR-141-3p/epidermal growth factor receptor axis^[102] and miR-196b-5p/fibroblast growth factor 2.^[103] In hypoxia-induced proliferative scars, NEAT1 binds miR-488-3p to upregulate collagen type III alpha 1 chain expression, increasing collagen deposition.^[104] Similarly, Wu et al^[105] found elevated expression of NEAT1 in human skin fibroblasts, which upregulates the fibroblast growth factor receptor substrate 2 (FRS2) by sponging miR-29-3p, promoting human skin fibroblasts proliferation and ECM release. Given the functions of NEAT1 across various wound-healing stages, NEAT1 could be used as a potent biomarker and treatment target to promote the recovery of chronic non-healing wounds and inhibit the scar-formation process.

Infectious diseases

LncRNAs play pivotal roles in immune responses to viral infections and host–pathogen interactions.^[106] Recent studies reveal that NEAT1 can either exhibit antiviral properties or facilitate viral replication.^[107–109] The expression of NEAT1 and the formation of paraspeckles are enhanced via herpes simplex virus type 1 (HSV-1) infection reliant on STAT3. NEAT1 is a scaffold that promotes interactions between paraspeckle proteins and viral genes, sequestering viral genes within paraspeckles. Thermosensitive gels containing NEAT1 small interfering RNA can effectively treat skin lesions in HSV-1-infected mice, suggesting that the targeted inhibition of NEAT1 can be used as a therapeutic approach to limit HSV-1 replication.^[110]

The roles of NEAT1 in skin diseases are shown in Table 1.

Table 1.

Roles of NEAT1 in skin diseases.

Skin diseases	LncRNA-NEAT1 expression	Pathogenic mechanisms of NEAT1
HA	Increase in HemEC	NEAT1/miR‑33a‑5p/HIF1α/NF‑κB axis[47] NEAT1/miR-361-5p/VEGF-A axis[48,49] NEAT1/miR-378b/FOSL1 axis[50,51]
Melanoma	Increase in melanoma cells, M2 macrophages	Upregulates RAB9A[53] Reverses the anti-tumor function of PPB[54] NEAT1/miR-495-3p/E2F3 axis[56,98] NEAT1/miR-200b-3p/SMAD2 axis[57] NEAT1/miR-23a-3p/KLF3 axis[58] NEAT1/miR-519c-3p/MeCP2 axis[59] NEAT1/miR-374a-5p/LGR4/IQGAP1 axis[61]
CSCC	Increase in CSCC cells	NEAT1/miR-361-5p/MMP1 axis[65] NEAT1/miR-342-3p/CUL4B/PI3K-AKT axis[66,67]
SLE	Increase in B cells, monocyte-derived dendritic cells, peripheral blood mononuclear cells	Activates B cells[72] Activates monocyte-derived dendritic cells[73] Disrupts the balance of Th1/Th2[74] Stimulates the activation of Th2 cells[75] Regulates cytokines and chemokines[76,77]
Psoriasis	Decrease in lesional skin	Leads to the hyperproliferation of KCs[81] NEAT1/miR-3194-5p/Galectin-7 axis[82]
	Increase in lesional skin and blood	May modulate immune regulation[83]
AD	Increase in serum	May act as a ceRNA within the NEAT1/miRNA/target network[92]
Rosacea	Increase in lesional skin	Targets specific miRNAs (hsa-miR-148b-3p, hsa-miR-148a-3p, hsa-miR-296-3p, hsa-miR-378g, and hsa-miR-152-3p) strongly associated with the upregulation/downregulation of certain mRNAs[94] NEAT1/miR-196a-5p/S100A9 axis[95]
Scar formation	Increase in keloid tissues, hypertrophic scar fibroblasts	NEAT1/miR-141-3p/EGFR axis[102] NEAT1/miR-196b-5p/FGF2 axis[103] NEAT1/miR-488-3p/COL3A1 axis[104] NEAT1/miR-29-3p/FRS2 axis[105]
Infectious diseases	Increase in the host cells of HSV-1	Sequesters viral genes within paraspeckles, promoting viral gene expression and replication[110]

AD: Atopic dermatitis; ceRNA: Competitive endogenous RNA; CSCC: Cutaneous squamous cell carcinoma; CUL4B: Cullin 4B; COL3A1: Collagen type III alpha 1 chain; EGFR: Epidermal growth factor receptor; E2F3: E2F transcription factor 3; FOSL1: FOS-like antigen 1; FGF2: Fibroblast growth factor 2; FRS2: Fibroblast growth factor receptor substrate 2; HA: Hemangioma; HemEC: HA endothelial cells; HIF1α: Hypoxia-inducible factor-1 alpha; HSV-1: Herpes simplex virus type 1; IQGAP1: IQ motif-containing GTPase-activating protein 1; KCs: Keratinocytes; KLF3: Krüppel-like factor 3; LGR4: Leucine-rich repeat-containing G protein-coupled receptor 4; MeCP2: Methyl CpG binding protein 2; miR-:microRNA-; MMP1: Upregulating matrix metallopeptidase 1; NF-κB: Nuclear factor kappa-B; PI3K-Akt: Phosphatidylinositol 3-kinase-protein kinase B; PPB: Polyphyllin B; RAB9A: Ras-related protein Rab-9A; SLE: Systemic lupus erythematosus; SMAD2: SMAD family member 2; S100A9: S100 calcium binding protein A9; Th1/Th2: T helper cell 1/ T helper cell 2; VEGF-A: Vascular endothelial growth factor A.

Challenges and Prospects

It is critical to acknowledge the limitations of existing research.

The complexity of gene regulatory networks

The pathogenic mechanisms of lncRNAs, including NEAT1, in skin diseases are highly complex. Although NEAT1 is consistently upregulated in most skin disorders, its expression in psoriasis remains controversial. This highlights the need for future studies to analyze cell-specific NEAT1 expression levels in diverse samples based on single-cell sequencing technology or multi-omics technology. Furthermore, high-throughput sequencing studies have uncovered lncRNA-mRNA co-expression networks in certain skin diseases, identifying several differentially expressed lncRNAs (including NEAT1) and mRNAs.^[92,94] These findings suggest that downstream events of NEAT1 may also be influenced by other lncRNAs, necessitating further exploration.

Lack of sufficient experimental evidence

Despite its potential, the therapeutic modulation of NEAT1 has not yet reached the stage of clinical application due to insufficient experimental evidence. For instance, ideal animal models for specific skin conditions, such as KDs, remain undeveloped. Additionally, research shows that NEAT1 depletion can produce differing outcomes in human versus murine cells. To improve the integrity and credibility of findings, basic experiments need to be conducted across a range of models, including 2D or 3D cell cultures, organoids, and in vivo systems. Emerging approaches, such as antisense oligonucleotides, small interfering RNA, clustered regularly interspaced shortpalindromic repeats-Cas9 technology, and small lncRNA-binding molecules offer promising methods to modulate NEAT1 function. Moreover, artificial lncRNA elements could potentially restore the function of diminished lncRNAs in a controlled spatial and temporal manner. However, further exploration of targeted delivery, therapeutic stability, adverse reactions, and safety is needed to achieve clinical translation.^[111]

Exploring isoform-specific functions of NEAT1

Isoform-specific functions of NEAT1 represent another critical research gap. While NEAT1_1 and NEAT1_2 have been shown to play distinct roles in some tumors,^[9] similar insights are largely absent in skin disease studies. In addition, studies summarized in this review showed that NEAT1 mainly acts as a ceRNA to exert pathogenic effects. As miRNA binds to various target mRNAs in the cytoplasm, sequestration of miRNA by NEAT1 should also occur in the cytoplasm. Previous studies demonstrate that NEAT1_1 can be transported to the cytoplasm and participate in cancer formation. Zhen et al^[112] found that the NEAT1_1/miR-338-3p/aldo-keto reductase family 1 member C1 axis mediates ferroptosis defense in lung adenocarcinoma. Some researchers believe that given the restriction of the nucleus, NEAT1_2 is unlikely to act as a ceRNA.^[28] However, NEAT1_2 was confirmed to sponge miR-106b-5p and indirectly regulate ATAD2.^[113] Therefore, the certain NEAT1 isoform that performs ceRNA functions remains unclear. Future research should focus on isoform-specific investigations of NEAT1 to clarify its role in skin diseases.^[38] Dong et al^[28] found that several approaches have been reported to detect the isoforms, including RNA-fluorescence in situ hybridization, dCas13 tagging, and nanopore direct RNA sequencing with NanoCount. Focusing on cellular expression and subcellular location of the two isoforms will assist in understanding the pathological mechanisms and developing precise targeted therapies.

Summary

With advancements in molecular biology techniques, lncRNAs, such as NEAT1, have emerged as valuable diagnostic biomarkers and therapeutic targets for various diseases. This review summarizes the gene regulation mechanisms of NEAT1 in skin disorders, such as the ceRNA network and epigenetic modulation, providing insight into its promising clinical utility. Preclinical therapeutic research summarized here includes: (1) Differential analysis of lncRNA using transcriptomic methods and multi-omics technology; and (2) functional validation through RNA interference (small interfering RNA targeting NEAT1 or short hairpin RNA targeting NEAT1), clustered regularly interspaced shortpalindromic repeats genome editing, and related approaches. Moving forward, research efforts should aim to unravel the full spectrum of NEAT1’s functions, facilitating its translation from bench to bedside to establish safe and effective targeted therapies.

Acknowledgements

We thank BioRender (https://www.BioRender.com/) for assistance with the illustration.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82073473, 82273559, and 82103757), and the Postdoctoral Research Project, West China Hospital, Sichuan University (No. 2020HXBH151).

Conflicts of interest

None.