A symphony of signals: the intricate role of lncRNAs in dermatological disorders

Abstract

The skin, as the body’s largest organ, relies on complex molecular networks to maintain homeostasis and repair damage. Recent advances in genomic research have highlighted the significance of long non-coding RNAs (lncRNAs), transcripts longer than 200 nucleotides, which act as key regulators of gene expression rather than mere transcriptional byproducts. Growing evidence suggests that lncRNAs influence critical signaling pathways, including PI3K/AKT/mTOR, Wnt/β-catenin, NF-κB, JAK/STAT, and TGF-β/SMAD shaping both normal skin biology and disease processes. This review synthesizes current knowledge on how to regulate the pathogenesis of dermatological conditions, including atopic dermatitis, psoriasis, vitiligo, systemic sclerosis, melanoma, and others. By outlining their potential roles as biomarkers and therapeutic targets, this work underscores the novelty and clinical relevance of lncRNA research in dermatology.

Introduction

Advances in genome analysis have revealed that more than 98% of the human genome is transcribed into non-coding RNAs (ncRNAs), while only about 2% encodes proteins [1–3]. Although ncRNAs do not translate into proteins, they regulate gene expression and influence the location and function of cellular components [2, 3]. Based on their structure and length, ncRNAs include circular RNAs (circRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) longer than 200 nucleotides [4, 5]. Moreover, lncRNAs can be further classified into enhancer, promoter-associated, intergenic (lincRNAs), intronic, sense, and natural antisense transcripts [6–8]. Notably, considered transcriptional byproducts [5], ncRNAs are now recognized as key regulators with strong tissue-specific expression patterns, making them promising biomarkers and therapeutic targets in neurodegenerative diseases, infection susceptibility, and cancers [1, 9–11]. Evidence increasingly points to their vital roles in skin biology and disease processes.

Furthermore, skin disorders affect more than one-third of the global population, ranking as the fourth leading cause of nonfatal disease burden [12–15]. The skin’s layered composition, epidermis, dermis, and hypodermis, provides the foundation for its barrier and protective roles [16, 17]. The epidermis contains progenitor cells, keratinocytes, and melanocytes, while the dermis hosts immune cells and fibroblasts that interact with keratinocytes to regulate homeostasis and hair follicle development [16, 18, 19]. Genomic studies suggest lncRNAs are central to epidermal stability, disease progression, and stress responses [19–21]. For instance, BC020554 and AK022798 exhibit differential expression during keratinocyte differentiation [22]. Among lncRNAs, TINCR [23] and H19 [22, 24] promote differentiation, whereas ANCR inhibits this process [5, 25–28], and MALAT1 regulates keratinocyte function [29].

LncRNAs also influence melanocyte activity and pigmentation. SPRIGHTLY (SPRY4-IT1) enhances melanocyte proliferation, while UCA1 reduces melanogenesis [22, 30–32]. Moreover, hair follicle stem cells play a vital role in sustaining skin and hair health, with lncRNA PlncRNA-1 (CBR3-AS1) promoting their proliferation and differentiation [33, 34]. In addition, other lncRNAs, including H19, RP11-766N7.3, and HOTAIR, alter dermal papilla cell function and impair follicle reconstruction by suppressing Wnt/β-catenin signaling [35]. Overall, lncRNAs are emerging as key regulators of skin biology whose dysregulation contributes to both inflammatory and malignant skin diseases. This review provides a comprehensive synthesis across diverse dermatological disorders, highlighting their novelty as biomarkers and therapeutic targets and underscoring their clinical importance in advancing precision dermatology.

Biology and function of lncRNAs

LncRNAs are single-stranded RNA molecules transcribed mainly by RNA polymerase II and undergo post-transcriptional modifications such as 5′-capping, splicing, and polyadenylation [36]. While they share similarities with mRNAs, lncRNAs are not translated into proteins. Some are rapidly degraded, whereas others remain stable [37, 38]. By definition, lncRNAs are longer than 200 nucleotides, which distinguishes them from shorter RNA species and excludes structural RNAs like 5S rRNAs, tRNAs, snRNAs, snoRNAs, as well as small RNAs such as miRNAs, siRNAs, and piRNAs [39]. However, some lncRNAs can be shorter than 200 nucleotides or act both as regulatory lncRNAs and as precursors of sncRNAs [8], suggesting the need for refined classifications. NcRNAs can be classified by size as small RNAs (< 50 nt), RNA polymerase III transcripts (50–500 nt), and lncRNAs (> 500 nt), most of which are produced through transcription by RNA polymerase II [40]. Additionally, lncRNAs are further categorized based on their genomic location [6–8].

LncRNAs include intergenic (lincRNAs), intronic, sense, and antisense transcripts, each defined by their genomic relationship to coding genes and exons [8, 41]. LincRNAs are transcripts that do not overlap with protein-coding genes [42] and frequently arise from cis-regulatory regions, including enhancers and promoters [43]. Enhancer-derived lncRNAs (eRNAs), like Evf2, are generally short, unstable, and bidirectional, and their transcription is strongly linked to enhancer activity [44, 45]. Promoter-associated lncRNAs, such as Myoparr, are typically antisense transcripts that regulate adjacent protein-coding genes involved in development [46–50]. Intronic lncRNAs arise from introns of protein-coding genes [8, 42], while sense and antisense lncRNAs are transcribed from the corresponding strands of protein-coding genes [8]. Circular RNAs (circRNAs) represent another class, generated by back-splicing of precursor mRNAs or lncRNAs, resulting in covalently closed structures lacking polyadenylation. CircRNAs can originate from intronic or exonic regions [51].

Functionally, lncRNAs act as versatile regulators of gene expression. They operate at multiple levels—epigenetic, transcriptional, post-transcriptional, translational, and post-translational [52]. For example, Evf-2, induced by Sonic Hedgehog, functions as a co-activator for the Dlx2 transcription factor during forebrain development [53]. LncRNAs may regulate nearby genes, as with TLS, which binds to lncRNAs to repress transcriptional co-factors at targets such as cyclin D1 [54]. They also influence transcription through chromatin remodeling and interactions with general transcription factors required for RNA polymerase II [55]. For instance, a lncRNA from the dihydrofolate reductase gene can form a triplex that blocks transcriptional co-factor binding [56]. Other ncRNAs, including U1 and 7SK, regulate transcription elongation to allow rapid stress responses [57–59]. Similarly, short interspersed nuclear elements (SINEs), such as Alu elements, can repress gene expression during environmental stress, whereas certain lncRNAs promote the activation of stress-responsive pathways [60–64]. Many lncRNAs transcribed by RNA polymerase III interact with transcription factors, revealing an additional regulatory network (Fig. 1) [65, 66].

Fig. 1.

Different lncRNAs role in human cellular functions. lncRNAs influence the expression of various genes and modulate cellular functions by regulating multiple intracellular signaling pathways, including PI3K, AKT, and NF-κB. PI3K: Phosphatidylinositol 3-Kinase—AKT: AKT Serine/Threonine Kinase 1—NF-κB: Nuclear Factor Kappa B – mTOR: Mechanistic Target of Rapamycin Signaling Pathway—TNF-α: Tumor necrosis factor alpha

In addition to their transcriptional roles, lncRNAs regulate post-transcriptional processes, including mRNA transport, splicing, translation, degradation, and miRNA neutralization [67–69]. They can also generate endogenous small interfering RNAs (endo-siRNAs), which suppress transposable elements and contribute to gene regulation [70–72].

Epigenetically, lncRNAs participate in histone and DNA methylation, influencing chromatin structure and gene expression [73, 74]. They have well-documented functions in X-chromosome inactivation [75], genomic imprinting [76], regulation of mRNA stability and decay [77], and the neutralization of miRNAs [78]. Imprinting is particularly associated with lncRNA-mediated chromatin modification, as seen with imprinted clusters such as Kcnqot1, which silence neighboring protein-coding genes [79, 80].

lncRNAs role in dermatologic disorders pathogenesis

The skin, the largest organ of the human body, accounts for nearly 15% of adult body weight and functions as a barrier against dehydration, radiation, physical injury, and pathogen invasion [81]. Recent evidence suggests that lncRNAs play a crucial role in various biological processes, including epigenetic regulation, transcriptional control, and post-transcriptional modification, with roles that extend from normal physiology to disease [82–84].

In skin biology, lncRNAs influence epidermal differentiation, melanogenesis, and the proliferation and differentiation of human hair follicle stem cells (HFSCs). They also enhance keratinocyte motility and contribute to wound healing through re-epithelialization [85]. Additionally, lncRNAs modulate fundamental cellular processes such as inflammation, proliferation, differentiation, and apoptosis, thereby driving the development of dermatologic disorders [83, 86]. Above all, dysregulated lncRNAs are increasingly recognized as contributors to chronic inflammatory skin diseases, including eczema, psoriasis, and lupus, as well as to malignancies such as melanoma [87]. Through their impact on immune regulation and inflammatory signaling pathways, lncRNAs emerge as key molecular players in the pathogenesis of both inflammatory and malignant skin diseases (Fig. 2).

Fig. 2.

lncRNAs role in the pathogenesis of dermatological disorders. lncRNAs play a significant role in the advancement of various dermatological conditions, including melanoma and psoriasis, by modulating inflammatory pathways, as well as influencing cell proliferation, migration, and metastasis. Furthermore, these lncRNAs have the potential to serve as therapeutic and diagnostic biomarkers within this framework

Psoriasis

Psoriasis is a chronic, immune-mediated inflammatory disorder affecting 2–3% of the global population. Multiple lncRNAs have been associated with Psoriasis risk and progression, highlighting their involvement in immune regulation and cutaneous inflammation. For instance, the first psoriasis-related LncRNA identified was PRINS, which is highly expressed in the non-lesional skin of patients compared to psoriatic plaques and healthy skin [88, 89]. Moreover, its expression increases in response to stressors such as UVB exposure and viral infection, including herpes simplex virus, and elevated PRINS subsequently alters keratinocyte stress responses while interacting with nucleophosmin (NPM) in psoriatic cells [90]. Additionally, it may also decrease keratinocyte apoptosis by regulating G1P3 [88]. Furthermore, another psoriasis-associated lncRNA, SPRR2C, is upregulated in lesional epidermis and in IL-22-treated HaCaT cells via the miR-330/STAT1/S100A7 axis [91]. More importantly, SPRR2C promotes pro-inflammatory cytokine production by competing with miR-330 to upregulate STAT1 and S100A7; this effect relies on the PI3K/AKT/mTOR pathway, as demonstrated by its reversal with the AKT inhibitor MK-2206 [92].

In addition, MiR31HG is also highly expressed in psoriatic keratinocytes, where NF-κB activation induces its upregulation, leading to G2/M cell cycle arrest [93]. Similarly, RP6-65G23.1 disrupts ERK1/2 and AKT signaling, altering apoptosis and growth and causing G1/S arrest [94].

Furthermore, the lncRNA FABP5P3 regulates KMT2C expression by binding the HuR protein; both are increased in psoriatic lesions [95]. As a result, stabilization of KMT2C mRNA promotes transcription of PIK3R3, influencing the PIK3R3/PKB/NF-κB pathway. Moreover, another upregulated lncRNA, KCNQ1OT1, enhances keratinocyte proliferation and migration under TNF-α stimulation by suppressing miR-183-3p, an effect reversed by GAB1 overexpression [96].

Additionally, the role of NF-κB signaling in psoriasis is well established [97, 98]. Interestingly, findings on UCA1 are conflicting. Ma et al. [30] reported that it is downregulated in psoriatic lesions, where it promotes A20 expression by inhibiting miR-125a, thereby suppressing NF-κB activity [30]. In contrast, Hu et al. [99] reported that UCA1 expression is increased, activating NF-κB signaling via HIF-1α and STAT3, with its effects further regulated by the m6A methyltransferase METTL14 [99].

Above all, the lncRNA MEG3 is downregulated in psoriatic keratinocytes, while miR-21 inhibits caspase-8 expression. Together, the MEG3/miR-21 axis regulates keratinocyte proliferation and apoptosis [100, 101]. Overexpression of MEG3 in TNF-α-treated cells reduced inflammation and promoted autophagy by inhibiting the PI3K/AKT/mTOR pathway [102].

Similarly, MIR181A2HG is downregulated in psoriasis, functioning as a sponge for miR-223-3p to regulate SOX6 expression [103, 104].

More importantly, serum levels of XIST are significantly higher in psoriasis patients than in controls, suggesting a role in keratinocyte proliferation and inflammation through the miR-338-5p/IL-6 axis [105]. Along with other upregulated lncRNAs, including GAS5, XIST, RP11-342L8.2, and PWAR6 (via miR-369-3p), correlate with higher PASI scores, reflecting disease severity [105–109]. Genetic studies implicate lncRNA variants in psoriasis susceptibility, with two SNPs in HOTAIR (rs12826786 and rs4759314) and three in ANRIL (rs1333048, rs4977574, rs10757278), both linked to increased disease risk [110, 111]. Taken together, lncRNAs play a vital regulatory role during psoriasis. Identifying disease-related lncRNAs in psoriasis patients may help establish new biomarker systems and find potential therapeutic targets. Collectively, these findings underscore the diverse regulatory functions of lncRNAs in psoriasis pathogenesis. Defining lncRNAs related to diseases can aid in the development of reliable biomarkers and contribute to the identification of novel therapeutic targets. Table 1 presents a summary of the key lncRNAs associated with psoriasis.

Table 1.

LncRNAs regulatory role in psoriasis

LncRNAs	Expression	Model	Target	Main findings	References
PRINS	Upregulated	Keratinocyte	G1P3	Reduces keratinocyte apoptosis susceptibility by regulating G1P3	[88]
		HaCaT and NHEK cell line, Keratinocyte	NPM	alters stress responses, potentially promoting psoriasis development via regulating NPM	[90] [89]
MSX2P1	Upregulation	HaCaT cell line	miR-6731-5p	inhibits miR-6731-5p, which regulates S100A7	[112]
SPRR2C	Upregulation	Ker-CT and HaCaT cell lines	PI3K/AKT/mTOR signaling pathway	induces the expression of several pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, CXCL2, and CCL20 through the PI3K/AKT/mTOR signaling pathway	[92]
	Upregulation	HaCaT cell line	miR-330	competes with miR-330, reducing its suppression of STAT1 and S100A7	[91]
MIR31HG	Upregulation	HaCaT cell line	NF-κB pathway	Influences cell cycle arrest at the G2/M phase and NF-κB pathway	[93]
RP6‐65G23.1	Upregulation	HaCaT and NHEK cell lines	Bcl-xl and Bcl2	Influences anti-apoptotic proteins and disrupts ERK1/2 and AKT signaling pathways	[94]
XIST	Upregulation	serum samples and HaCaT cell line	miR-338-5p	influences keratinocyte proliferation and inflammation via the miR-338-5p/IL-6 pathway	[105]
HOTAIR	Upregulation	HaCaT cell line	miR-126	lncRNA-HOTAIR/miR-126 axis may regulate psoriasis progression via increasing cleaved caspase-3 expression and the cleaved caspase-3/caspase-3 ratio	[113]
KLHDC7B-DT	Upregulation	keratinocyte	ILF2	Directly interacts with ILF2 and STAT3/JNK signaling pathways	[114]
FABPSP3	Upregulation	Keratinocyte	HuR and KMT2C	Modulates KMT2C expression via binding to the HuR protein, impacting the PIK3R3/PKB/NF-κB pathway	[95]
AGAP2-AS1	Upregulation	Keratinocyte	miR-424-5p	Affects miR-424-5p/AKT/mTOR pathway	[115]
GDA-1	Upregulation	NHEKs and Ker-CT cell lines	FOXM1	Regulates FOXM1 expression and activates the STAT3/NF-κB pathways	[116]
BLACAT1	Upregulation	psoriasis tissue	miR-149-5p	Acts as a competing endogenous RNA (ceRNA) that sponges miR-149-5p and regulates AKT1 expression	[117]
SH3PXD2A-AS1	Upregulation	HaCaT cell line	miR-125b	downregulates miR-125b and its silencing promotes cleaved-caspase-3 protein levels and inhibited S100A7, TNF-α, IL-6, p-STAT3, STAT3, CyclinD1, and surviving protein levels
		Skin sample	miR-125b	participates in the STAT3/SH3PXD2A-AS1/miR-125b/STAT3 positive feedback loop and is recognized as part of the IFN-γ signaling pathway regulation	[118]
		HaCaT cell line	Hsa‐miR‐665	Modulates IFN‐γ and JAK/STAT signaling pathway	[119]
KCNQ1OT1	Upregulation	HaCaT cell line	miR-183-3p	affects keratinocyte proliferation and migration, especially under TNF-α stimulation, by regulating miR-183-3p	[96]
LINC01176	Upregulation	Mouse model	miR-218-5p	Enhances the multiplication and spread of keratinocytes while preventing apoptosis by influencing miR-218-5p, which functions as a suppressor of the IL-36G linked to psoriasis	[120]
NEAT1	Upregulation	HaCaT cell line	miR-3194-5p	positively influences the expression of Galectin-7 by targeting miR-3194-5p	[121]
		Psoriatic Epidermis		is expressed in all cell types of the skin	[122]
NORAD	Upregulation	HaCaT cell line and Mouse model	miR-26a	Leads to the downregulation of miR-26a and lower levels of CDC6, which further causes overexpression of proteins associated with keratinocyte proliferation (K6, K16, and K17)	[123]
SPRR2G-2	Upregulation	keratinocyte	KHSRP	Regulates cell proliferation and apoptosis while promoting psoriasis-related proteins and cytokines linked to the STAT3 pathway, including S100A7, IL-1β, IL-8, and CXCL10. It also influences KHSRP, which controls the decay of mRNA for these cytokines	[124]
AGXT2L1-2:2	Upregulation	keratinocyte	ERRα	promotes keratinocyte proliferation and inhibits cell apoptosis via ERRα	[125]
PRANCR	Upregulation	Keratinocyte	total and nuclear CDKN1A (also known as p21)	PRANCR regulates 1136 genes linked to the late cell cycle with a CHR promoter element. Its depletion raises p21 levels, essential for keratinocyte proliferation and differentiation	[126]
Lnc-HSFY2-10:1	Upregulation	Skin sample	miRNA − 145	Regulates microRNA-145, negatively impacting cell proliferation and proinflammatory cytokine release by inhibiting NF-κB and mTOR downstream genes	[127]
Lnc-POLR3E-3:3	Downregulated	Skin sample	IRF1	Lnc-POLR3E-3:3 (downregulated) may regulate T regulatory (Treg) cell differentiation by influencing irf1, which is proven to inhibit Forkhead box P3 in mice[128]	[127]
ENST00000557691	Upregulated	Skin sample	mapk kinase kinase 9	MAPK signaling pathway	[127]
Lnc-PERP-2:7	Downregulated	Skin sample	mapk kinase kinase 9	MAPK signaling pathway	[127]
PRKCQ‐AS1	Upregulation	HaCaT cell line	miR‐545‐5p	Regulates JAK/STAT pathway genes by competing for miR-545-5p	[119]
TRAF3IP2-AS1 A4165G (rs13210247)	Upregulation	Six- to eight-week-old female C57BL/6 or BALB/c mice	SRSF10	Modulates the expression of Act1 and IL-17A signaling by attracting SRSF10, which reduces the levels of IRF1, a transcription factor for Act1	[129]
TRAF3IP2	Upregulation	Keratinocyte	Act1	Encodes TRAF3 interacting protein 2 (ACT1), which plays a role in IL-17 signaling and interacts with Rel/NF-κB transcription factor family members	[130]
MEG3	Downregulation	Psoriatic mice	PI3K, AKT,mTOR signaling pathway	Reduces inflammation and promotes autophagy by inhibiting the PI3K/AKT/mTOR pathway	[102]
		Skin sample	miRNA-21	inhibits miR-21, which inhibits caspase-8 levels	[101]
UCA1	Upregulation	HaCaT cells	METTL14 and the HIF-1α/NF-κB axis	activates the NF-κB signaling pathway, influenced by HIF-1α and STAT3, and interacts with METTL14	[99]
	Downregulation	Skin sample	miR125a	negatively regulates NF-κB via the miR-125a-A20 axis	[30]
CERNA2	Upregulation	HaCaT cell line	HaCaT cell line	Modulates IFN‐γ and JAK/STAT signaling pathway	[119]
	Upregulation	Skin sample	microRNA let-7b	Regulates IFN-γ and JAK/STAT signaling pathways	[118]
MIR181A2HG	Downregulation	HaCaT cell line	SRSF1	negatively regulates HaCaT keratinocyte proliferation by binding SRSF1	[103]
		keratinocyte	miR-223-3p	acts as a miR-223-3p sponge targeting SOX6	[104]
AL162231.4	Downregulation	Skin samples	CCL27	modulates CCL27 expression	[131]
Uc.291	Downregulation	Skin samples	ACTL6A	Upregulates ACTL6A	[132]
LOC285194	Downregulation	Keratinocyte	miR-616	inhibits the proliferation of human keratinocytes via modulating the miR-616/GATA3 pathway	[133]
H19	Downregulation	HaCaT cell line	miR-766-3p	The lncRNA H19/miR-766-3p/S1PR3 pathway plays a role in the excessive growth of keratinocytes and skin inflammation in psoriasis through the AKT/mTOR signaling pathway	[134]
LINC00941	Downregulation	keratinocyte	SPRR5	The lncRNA LINC00941/SPRR5 axis regulates keratinocyte differentiation by repressing SPRR5, and its downregulation induces premature epidermal differentiation through activation of EDC genes	[135]

HaCaT: Human Adult Keratinocyte Cell Line—NHEK: Normal Human Epidermal Keratinocytes—IL: Interleukin—miR: MicroRNA—lncRNA: Long Non-Coding RNA—STAT: Signal Transducer and Activator of Transcription—AKT: Protein Kinase B—mTOR: Mechanistic Target of Rapamycin—PI3K: Phosphoinositide 3-Kinase—Bcl-xL/Bcl2: B-cell lymphoma 2 family proteins—CXCL: C-X-C Motif Chemokine Ligand—CCL: C–C Motif Chemokine Ligand

Vitiligo

Vitiligo is a long-term skin disorder marked by the loss of pigmentation due to the destruction of melanocytes, affecting an estimated 0.2–1.8% of people worldwide. While its exact underlying mechanisms remain unclear, research indicates that genetic, neurological, and immune-related factors all play roles in its development [136–139]. Furthermore, recent studies have highlighted the crucial role of lncRNAs in controlling gene transcription during inflammatory processes. Moreover, abnormal patterns of their expression have been linked to the immune-related development of chronic inflammation, cancer, and various other disorders [137].

More importantly, the study by Pang et al. proved the upregulation of 32 lncRNAs, while 78 lncRNAs exhibited decreased expression in the vitiligo skin lesions [139]. These differentially expressed lncRNAs were co-expressed with genes such as DCT, TYR, and TYRP1, which play a crucial role in melanogenesis. The interactions between these lncRNAs and their target genes may influence pigmentation and melanocyte survival, highlighting their correlation with vitiligo pathogenesis [139].

Moreover, LOC100506314 interacts with STAT3 and MIF, resulting in the inhibition of STAT3 and NF-κB signaling. This inhibition suppresses phosphorylation of STAT3, AKT, and ERK, and reduces p65 levels. In vitiligo patients, LOC100506314 was overexpressed in T cells, which lowered the production of proinflammatory cytokines IL-6 and IL-17—both elevated in this disease—highlighting its role in vitiligo-associated inflammation [137].

Above all, Mir17hg showed significant downregulation in mice exposed to chronic restraint stress (CRS), which was related to reduced activity of melanogenesis proteins TYR and TRP2. Additionally, in human tissues, Mir17hg was likewise downregulated. This lncRNA promotes melanin synthesis by suppressing TGFβR2 and regulating the TGF-β/SMAD and PI3K/AKT/mTOR pathways. Its reduced expression, together with psychological stress, highlights its role in the pathogenesis of vitiligo [138].

Furthermore, the miR-375/GATA3 pathway, regulated by FOXO3, facilitates the pro-survival impact of TUG1 on melanocytes. Its increased expression in patients with vitiligo further enhanced melanocyte survival while restricting the migration of CD8 + T-cells, indicating that this pathway could serve as a promising therapeutic target for vitiligo [140].

Moreover, LOC100506314 was associated with the Signal Transducer and Activator of Transcription 3 (STAT3) and Macrophage Migration Inhibitory Factor (MIF). It inhibited the phosphorylation of STAT3, AKT, and ERK by suppressing STAT3 and NF-κB signaling pathways, thereby reducing p65 expression [141]. In addition, LOC100506314 was overexpressed in the T cells of vitiligo patients, leading to a reduction in the production of proinflammatory cytokines IL-6 and IL-17. These cytokines are known to be elevated in individuals with vitiligo, thereby underscoring the significance of LOC100506314 in the inflammatory responses associated with this condition [141].

Additionally, MALAT1 acts as a negative regulator of miR-211, which exhibits reduced expression in the epidermis of individuals with vitiligo. This regulation increases the expression of SIRT1, an NAD-dependent deacetylase that promotes keratinocyte differentiation [142]. Besides, by increasing SIRT1 expression, MALAT1 reduces CPD formation and thereby protects keratinocytes from UVB-induced DNA damage. The MALAT1–miR-211–SIRT1 pathway emerges from these findings as a pivotal mechanism linking vitiligo pathogenesis with keratinocyte resistance to UV damage [142]. Table 2 summarizes the lncRNAs associated with vitiligo pathogenesis (2).

Table 2.

lncRNAs regulatory role in vitiligo, behçet’s Disease, systemic sclerosis and dermatomyositis

lncRNAs	Diseases	lncRNA expression	Model	Target	Main findings	References
Multiple	Vitiligo	32 upregulated, 78 downregulated; 14 aberrantly expressed	Human skin lesions	Melanogenesis-related genes (DCT, TYR, TYRP1)	↑/↓ lncRNAs → melanogenesis-related genes (DCT, TYR, TYRP1) through co-expression networks Abnormally expressed lncRNAs → melanocyte function and melanogenesis in vitiligo Dysregulated lncRNA-mRNA networks → potential diagnostic or therapeutic targets for vitiligo	[139]
TUG1	Vitiligo	Down	VP serum and tissue samples	miRNA-377, PPAR-γ, IL-17	↓ TUG1 → ↑ miRNA-377, IL-17 → in VP ↓ PPAR-γ → in VP Dysregulation of TUG1, miRNA-377 → vitiligo pathogenesis → ↓ PPAR-γ and ↑ IL-17	[143]
MALAT1	Vitiligo	Up	VP serum and biopsy samples	miR-9	↑ MALAT-1 → ↑ miR-9 → in VP serum and biopsy samples Positive correlation → MALAT-1, miR-9 expression levels MALAT-1, miR-9 → potential biomarkers for vitiligo susceptibility → new therapeutic directions	[141]
MALAT1	Vitiligo	Up	VP keratinocytes	miR-211, SIRT1	↑ MALAT1 → suppresses miR-211, → ↑ SIRT1 SIRT1 → promotes differentiated keratinocytes → protects from UVB-induced DNA damage → potentially contributing to vitiligo pathology	[144]
TUG1	Vitiligo	Down	Human skin lesions	miR-375, GATA3, FOXO3	↓ TUG1 and ↑ miR-375 → in VP TUG1 → enhances melanocyte survival, inhibits CD8 + T cell migration FOXO3 →  + regulates TUG1 expression → promotes melanocyte survival TUG1 → ↑GATA3 → targeting miR-375 → a TUG1/miR-375/GATA3 axis	[140]
Multiple	BD	Allele-dependent	Human skin lesions	Genetic variants in the MHC region, including HLA-B/MICA-associated loci	908 novel transcripts in the human MHC region, including 119 novel long intergenic noncoding RNAs, 593 novel isoforms of known genes Genetic variants in the HLA-B/MICA region → located within lncRNAs → expressed from the protective haplotype the complex regulatory network of the MHC region → role in disease risk	[145]
LOC107984558	BD		Human skin lesions	rs9517723 polymorphism in LOC107984558; UBAC2 gene expression	The T allele of rs9517723 in LOC107984558 → ocular and CNS lesions in BD rs9517723 TT homozygotes → ↑ UBAC2 ↑UBAC2 → TT risk allele → overactivate the ubiquitination-related pathway → BD-related ocular and CNS lesions	[146]
NEAT1	BD	Down	Human skin lesions	miR-21, IL-17	↓ NEAT1, miR-21 → ↑ IL-17 in BD patients IL-17 → major vessel involvement, cyclophosphamide intake NEAT1 →—correlate with colchicine intake NEAT1, miR-21, and IL-17 → BD pathogenesis → potential biomarkers or therapeutic targets	[147]
MIAT, PVT1	BD	Down up	Serum of BD and HC	miR-93-5p, miR-124-3p, SOD-2, MICA	↑ PVT1, miR-93-5p → BD pathogenesis ↓ MIAT, miR-124-3p, SOD-2, MICA → BD progression selected RNAs → diagnostic biomarkers for BD RNA expression → predict BD ↑ TNF-α levels in BD	[148]
MEG3, MAFG-AS1	BD	Down	serum of BD and HC	miRNA 147-b	↓ MEG3, MAFG-AS1, ↑ miRNA 147-b → BD pathogenesis MEG3, MAFG-AS1, and miRNA 147-b can differentiate BD from controls with high sensitivity (76%, 100%, 70%) and 100% specificity MEG3 → predictor for new ocular involvement in BD MEG3, MAFG-AS1, and miRNA 147-b → diagnostic markers and therapeutic targets for BD	[149]
MALAT1	SSc		Mouse:SSc mouse model vs. normal mice	miR-206, let-7a-5p, miR-196a-5p; CCL2, IL6, SERPINE1	MALAT1 → regulates CCL2 → miR-206, → SSc pathogenesis let-7a-5p → IL6 expression → immune-related processes in SSc miR-196a-5p → modulates SERPINE1 → fibrosis and Predicted candidate drugs for SSc: TIPLASININ, CARLUMAB, BINDARIT	[150]
H19	SSc	Up	serum of SSc and HC	miRNA-133, PKM2, TGF-β	↓ miRNA-133 → in SSc patients ↑ H19, PKM2, and TGF-β → in SSc patients correlations between H19, TGF-β, miRNA-133, and PKM2, → role of H19 in SSc pathogenesis miRNA-133, H19, PKM2, and TGF-β → diagnostic biomarkers	[151]
MALAT1, NEAT1	SSc	Up	Plasma and WBCs of SSc and HC	miR-30e-5p, miR-30a-5p, CHI3L1 (YKL-40)	↓ miR-30e-5p → WBCs, ↓ miR-30a-5p → in plasma of SSc patients ↑ MALAT1 and NEAT1 → in WBCs of SSc patients MALAT1 and NEAT1 → miR-30e-5p and miR-30a-5p decoys, → ↓ miR-30e/miR-30a-5p Dysregulated lncRNA/miRNA axis → ↑ CHI3L1, an inflammation-associated glycoprotein → SSc pathogenesis	[152]
Multiple	SSc		Lung tissue	miRNAs, core mRNAs	35 differentially expressed miRNAs (DEmiRs), 142 differentially expressed mRNAs (DEMs), and 1,265 target genes of DEmiRs in SSc-ILD lung tissue ceRNA network including 9 DEmiRs, 9 core mRNAs, and 51 predicted lncRNAs 9 immune cell types differentially expressed in lung tissue between SSc-ILD patients and controls  + and—correlations between core mRNAs (and infiltrating immune cells	[153]
OTUD6B-AS1	SSc	Down	Skin tissue	Cyclin D1, OTUD6B	↓ OTUD6B-AS1, OTUD6B → in SSc ↓ OTUD6B-AS1 ↑ Cyclin D1,↓ Proliferation and suppressed apoptosis Highlights a novel apoptosis resistance mechanism in fibroblasts and vascular smooth muscle cells → relevant to SSc pathogenesis	[154]
ENST00000584157.1, ENST00000523380.1, ENST00000560054.1	DM	Up	HSkMCs	miRNAs (hsa-miR-125a-3p, hsa-miR-1246, hsa-miR-3614-5p)	↑ DE lncRNAs and miRNAs → induced autophagy in HSkMCs Plasma EXOs from DM → linked to muscle damage through regulation of autophagy, IFN-β production, and mTOR signaling DE miRNAs and lncRNAs → biomarkers and therapeutic targets in DM	[155]
HAGLR	DM	Up	Human skin lesions and in vivo experiments with adv-HAGLR injection	RUNX3, Foxp3	↑HAGLR → ↓Foxp3, RUNX3 protein levels, → ↓Treg cell proportions ↓ HAGLR → restored Treg cell → ↑RUNX3 and Foxp3 expression Injection of adv-HAGLR in vivo → ↑Treg cells and attenuated DM progression HAGLR + RUNX3, regulated Foxp3 transcription → Treg cell differentiation and DM pathogenesis	[156]
Multiple	DM	Up/Down	HDMECs, HSkMCs, EXOs	PI3K-Akt, MAPK, AMPK, FoxO signaling pathways	124 ↑and 255 ↓lncRNAs, 17 ↑and 15 ↓miRNAs, in DM neutrophil EXOs DE lncRNAs, miRNAs → interleukin-6, interferon-beta production, skeletal muscle cell proliferation and differentiation, and endothelial cell development Neutrophil EXOs contribute to DM through these lncRNAs and miRNAs in key signaling pathways	[157]
Multiple	DM	Up/Down	DM muscle tissue	Type 1 interferon signaling, USP18	1198 lncRNAs, 1213 mRNAs → differentially expressed in DM patients DM patients → dysregulation in type 1 interferon signaling linc-DGCR6-1 → regulator of USP18, a type 1 interferon-inducible gene → ↑perifascicular muscle fibers in DM patients	[158]
AL136018.1	DM	Up	Quadriceps femoris tissues of DM patients	CTSG, DNMT3a	↑AL136018.1 → in skeletal muscle tissues of DM patients →  + correlated with CTSG transcription and gene body DNA methylation in vivo AL136018.1–201 recruits DNMT3a to the gene body → DNA methylation, enhancing CTSG transcription Gene body methylation, regulated by AL136018.1, facilitates CTSG transcription in DM	[159]

HSkMCs: Human skeletal muscle myoblasts cells—HDMECs: Human dermal microvascular endothelial cells—EXOs: DM neutrophil exosomes—DE: Differentially expressed—LncRNA: long non-coding RNA—DM: Dermatomyositis—CTSG: Cathepsin G—BD: Behçet’s Disease—SSc: Systemic Sclerosis—TUG1: Taurine Upregulated Gene 1—MALAT-1: Metastasis-Associated Lung Adenocarcinoma Transcript 1—HAGLR: Homeobox D gene cluster antisense growth-associated long noncoding RNA—DNMT3a: DNA Methyltransferase 3 Alpha—USP18: Ubiquitin Specific Peptidase 18—PI3K-Akt: Phosphoinositide 3-Kinase—Protein Kinase B (Akt)—MAPK: Mitogen-Activated Protein Kinase—AMPK: AMP-Activated Protein Kinase—FoxO: Forkhead Box O—RUNX3: Runt-related transcription factor 3—OTUD6B-AS1: OTU deubiquitinase 6B antisense RNA 1—WBC: White Blood Cells—NEAT1: Nuclear Enriched Abundant Transcript 1—miR-30a-5p: MicroRNA-30a-5p—CHI3L1: Chitinase 3-like 1—PVT1: Plasmacytoma Variant Translocation 1—MEG3: Maternally Expressed Gene 3

Behçet’s disease (BD

Behçet’s disease (BD) is a rare multisystem inflammatory disorder marked by recurrent mucocutaneous ulcers, ocular inflammation, and, in severe cases, vascular, neurological, or gastrointestinal involvement [160]. However, etiopathogenesis remains unclear, though infections, microbiome alterations, and genetic susceptibility—particularly the strong link to HLA-B51—are implicated. Besides, non-coding RNAs (ncRNAs)—including miRNAs, lncRNAs, and circRNAs—are now regarded as key regulators of immune dysregulation and inflammation in BD pathogenesis [160].

In BD patients, Mehana et al. found increased expression of lncRNA MEG3, which influenced the balance between the anti-inflammatory Treg/FOXP3 pathway and the pro-inflammatory Th17/RORγt pathway [161]. This effect extended to associated cytokine networks, enhancing TGF-β and IL-10 while modulating IL-17 and IL-23 [161].

Moreover, lncRNA NEAT1 activates the inflammasome and drives caspase-1 activation, thereby increasing the secretion of pro-inflammatory cytokines such as IL-6 and CXCL10. Although, exacerbates inflammation through the MAPK pathway, influencing both inflammatory signaling and immune responses [162]. Additionally, increased levels of NEAT1 have been associated with clinical manifestations such as skin lesions, vascular complications, neurological symptoms, and joint inflammation, highlighting its significance in the progression of BD [162].

More importantly, lncRNA NEAT1 elevated IL8 expression and STAT3 activity, both of which are essential for the T-helper 17 (Th17) differentiation [163]. This regulation affects innate immunity and plays a critical role in maintaining immune balance and controlling inflammation in BD. Above all, NEAT1 downregulation in BD patients highlighted its potential role in BD pathogenesis [163]. In addition, Lnc-DC plays a crucial role by binding to STAT3 and promoting its phosphorylation, thereby enhancing the transcription of immune-related genes and increasing the production of cytokines such as TNF-α, IFN-γ, IL-12, and IL-21 [162]. This enlargement in cytokine activity disrupts the balance between Th17 and Treg cells, thus contributing to immune responses. As a result, lnc-DC acts as a regulator of dendritic cell-mediated immune responses through the STAT3 pathway and is involved in the development of BD by amplifying inflammatory cascades [162].

Furthermore, lncRNAs MIAT and PVT1 interact with microRNAs such as miR-93-5p and miR-124-3p, thereby regulating the expression of mRNAs including SOD-2 and MICA, which are central to oxidative stress and immune regulation pathways [148]. In BD patients, the elevated levels of PVT1 and miR-93-5p, coupled with the reduced expression of MIAT, miR-124-3p, SOD-2, and MICA, disrupt these critical pathways and lead to increased inflammatory responses, as indicated by higher serum levels of TNF-α. These findings underscore the essential role of these lncRNAs in the pathogenesis of BD [148].

Above all, Linc00467, a lncRNA, demonstrated increased expression in peripheral blood mononuclear cells (PBMCs) and CD4 + T cells of patients with BD, which resulted in enhanced survival of CD4 + T cells, highlighting the role of these lncRNAs in BD pathogenesis [164]. Mechanistically, Linc00467 was identified as a binding partner of the RNA-binding protein HUR, indicating that HUR is integral to the consequences associated with linc00467. Additionally, the rs12569232 SNP, therefore, affected the development of BD by altering the expression of linc00467 and its interaction with HUR [164]. Table 2 provides a summary of several key lncRNAs implicated in dysregulation in BD.

Systemic sclerosis

Systemic sclerosis (SSc) is a rare, chronic autoimmune disorder of connective tissue that manifests with widespread vascular abnormalities, fibroblast overactivation, excessive deposition of extracellular matrix (ECM) proteins, and persistent immune system dysregulation [165]. Although the exact causes of SSc remain unclear, environmental exposures such as silica and organic solvents have been implicated in its onset. Epigenetic alterations, including DNA hypomethylation, histone modifications, and the regulation by lncRNAs, also play a crucial role in disease progression [165].

For instance, Abd-Elmawla et al. identified four lncRNAs—HOTTIP, TINCR, SPRY4-IT1, and ANCR—as key players in SSc progression [166]. Among them, HOTTIP and SPRY4-IT1 interact with fibrosis-related pathways, including the TGF-β/SMAD axis and other pro-fibrotic signaling cascades. Besides, their elevated expression in SSc patients showed a positive correlation with the modified Rodnan skin score, indicating a potential role in driving the fibrotic processes characteristic of the disease [166]. In contrast, ANCR downregulation impaired keratinocyte differentiation and activated collagen synthesis pathways, underscoring its anti-fibrotic function [166]. Additionally, TINCR upregulation was associated with higher erythrocyte sedimentation rate (ESR) values, suggesting its contribution to systemic inflammation through cytokine regulation [166].

In this context, lncRNA-H19 interacted with microRNAs, affecting differentiation, cell proliferation, and ECM production. It was also determined that H19 can influence glycolysis by activating PKM2, an essential enzyme in the glycolytic pathway that aids in ECM deposition and the activation of mesenchymal cells, which are key features of fibrosis [151]. Additionally, H19 is inversely associated with TGF-β levels, a major contributor to fibrosis. Crucially, H19 influences immune signaling, including the Wnt/β-catenin pathway that promotes fibroblast activity. Collectively, the evidence highlights H19 as a crucial regulator in SSc pathogenesis [151].

Moreover, the lncRNA TSIX activated the TGF-β signaling pathway and improved the stability of type I collagen mRNA, particularly the α1(I) and α2(I) subunits [167]. Through this process, extracellular matrix accumulation occurs, a defining feature of SSc-related fibrosis. Notably, TSIX knockdown via siRNA diminished collagen mRNA stability, highlighting its role in post-transcriptional regulation. Additionally, elevated levels of TSIX in the serum of SSc patients emphasized its importance in SSc development [167].

Furthermore, lncRNA HOTAIR promotes tissue fibrosis in SSc by enhancing collagen synthesis and activating fibroblasts [168]. This effect occurs through the repression of target genes by recruiting chromatin-modifying complexes such as EZH2, which catalyzes histone methylation (H3K27me3). Additionally, by downregulating miR-34a, HOTAIR activates the Notch pathway, resulting in defective angiogenesis [168].

More importantly, the Negative Regulator of the IFN Response (NRIR) functioned through the IFN signaling pathway by modulating the expression of IFN-stimulated genes (ISGs), such as the chemokines CXCL10 and CXCL11 [169]. Furthermore, NRIR was significantly upregulated in monocytes from patients with SSc, and its knockdown led to a decrease in the production of these chemokines. These results indicate that NRIR plays a vital role in immune activation and inflammation, key features of SSc pathogenesis [169].

Above all, lncRNA ncRNA00201 was downregulated in SSc patients, causing fibrosis, vascular abnormalities, and immune activation by targeting miRNAs that regulate key genes involved in TGF-beta signaling, PI3K/mTOR, p38 MAPK, and TLR pathways [170]. In addition, researchers also highlighted its impact on cancer-associated genes, revealing overlapping molecular pathways. These findings marked the role of lncRNA ncRNA00201 in SSc pathogenesis [170]. In Table 2, we outline several lncRNAs whose expression is dysregulated in SSc.

Dermatomyositis

Dermatomyositis (DM) is a chronic autoimmune disorder characterized by distinct cutaneous manifestations and progressive, symmetrical muscle weakness [157, 158]. Histopathological hallmarks of DM include inflammatory cell infiltration and perifascicular atrophy [157]. Although its precise etiopathogenesis remains incompletely understood, multiple factors contribute to disease development, including dysregulated gene expression, MHC polymorphisms, aberrant type I interferon (IFN) signaling, and epigenetic modifications [157, 158]. Among these, long non-coding RNAs (lncRNAs)—RNA transcripts longer than 200 nucleotides with no coding capacity—have emerged as important regulators in DM pathogenesis [157–159].

For instance, in a pivotal study, Peng et al. identified 1198 differentially expressed lncRNAs in DM patients (322 upregulated and 876 downregulated) [158]. Notably, they observed increased expression of USP18, a type I IFN–inducible protein, in muscle tissue within areas of perifascicular atrophy. Further investigation revealed that linc-DGCR6-1 functions as a regulator of USP18 expression, underscoring its importance in DM progression [158].

Moreover, regulatory T (Treg) cells have been established as key players in modulating immune tolerance and suppressing autoimmunity. Their deficiency is associated with chronic inflammation and muscle tissue damage, which are prevalent characteristics of dermatomyositis [156]. Besides, the number of Treg cells decreased in DM patients; however, their levels increased following treatment. Above all, the overexpression of lncRNA HAGLR has been associated with the downregulation of FOX3, a crucial transcription factor involved in regulating Treg cells, leading to a reduction in the proportions of Treg cells. These findings suggest that lncRNA HAGLR may play a significant role in the progression of DM [156].

Furthermore, the role of lncRNAs in TRIM33 regulation has also been elucidated. Interactions with PAXBP1-AS1, NNT-AS1, LINC01206, and MKLN1-AS alter TRIM33 splicing, generating alternative isoforms of TIF1γ, a protein central to DM-associated autoimmunity [171]. Moreover, dysregulated lncRNAs act as competing endogenous RNAs (ceRNAs), sequestering miR-142-3p, which enhances TRIM33 expression and disrupts the balance between Th17 and Treg cells. This imbalance drives autoimmune responses and inflammation characteristic of DM [171]. Besides lncMIPOL1-6 and lncDDX47-3 modulate chemokine expression, enhancing Th1-driven responses and facilitating immune cell infiltration into muscle tissue, thereby sustaining the pro-inflammatory milieu characteristic of DM [172].

Additionally, another key lncRNA, AL136018.1 (AL-1), directly interacts with Cathepsin G (CTSG), enhancing its expression in skeletal muscle of DM patients [159]. Moreover, CTSG expression is also influenced by DNMT3a-mediated DNA methylation at CpG sites in exons and introns, linking lncRNA regulation to epigenetic modification in DM pathology [159].

In addition, individual lncRNAs, network-based analyses have revealed that lncRNAs function within ceRNA networks, modulating critical genes such as GIMAP6, COG8, C1orf106, IFI6, and EVPL [173]. These regulatory interactions suggest that lncRNAs act as sponges for miRNAs, influencing mRNA expression related to CD4 + T cell activity and infiltration in DM muscle. Moreover, lncRNAs participate in signaling cascades, including the JAK/STAT pathway, further emphasizing their central role in immune dysregulation and disease progression. Collectively, these findings highlight lncRNAs as crucial modulators of immune pathways, epigenetic regulation, and inflammatory signaling in DM. Their involvement not only provides insight into disease mechanisms, but also positions them as promising biomarkers and therapeutic targets. Table 2 summarizes key lncRNAs with dysregulated expression in SSc and their pathogenic relevance.

Alopecia areata

Alopecia areata (AA) is an autoimmune disorder that typically manifests as sudden, non-scarring patches of hair loss, developing when the immune system mistakenly targets hair follicles, resulting in localized or widespread bald spots that are round or irregular in shape [174]. Although the scalp is most commonly affected, AA can also involve the eyebrows, eyelashes, beard, or other organs with hair [175]. Clinically, AA is considered a chronic, tissue-specific autoimmune condition [176]. Besides, severe subtypes of AA include alopecia totalis, characterized by complete scalp hair loss; alopecia universalis, involving the loss of all body hair; and ophiasis, defined by a distinctive band-like pattern of hair loss along the occipital and temporal regions [177, 178]. The global prevalence of AA is estimated at 0.1% to 0.2%, and approximately 1.7% of the population is at lifetime risk of developing AA or related autoimmune disorders [179]. In addition to visible hair loss, AA has been linked to comorbidities such as mental health conditions, including depression and anxiety, as well as cardiovascular disease [180].

Furthermore, lncRNAs have emerged as key contributors to the pathogenesis of alopecia areata [181]. Acting as potent epigenetic regulators, they can either suppress or activate genes involved in immune regulation and inflammation. They modulate immune responses by activating or repressing gene expression through mechanisms such as protein interactions, chromatin remodeling, and microRNA sequestration [181]. For instance, HOTAIR, a well-characterized lncRNA, regulates immune and inflammatory gene expression by recruiting PRC2 and LSD1 to modify histones and by activating the NF-κB and STAT3 pathways. Its elevated expression in alopecia areata has been linked to enhanced immune activity and hair follicle destruction. Similarly, MALAT1 contributes to disease progression by activating the PI3K/Akt pathway and upregulating cytokines such as TNF-α and IL-6 [181]. In addition, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is another key lncRNA [181]. More importantly, NEAT1, involved in several autoimmune diseases, is also implicated in AA. By stimulating the NF-κB pathway and promoting the expression of IL-8 and IFN-γ, NEAT1 enhances local inflammation and hair follicle damage. Elevated NEAT1 expression has been observed in skin biopsies of AA patients, suggesting its potential as a diagnostic biomarker [182].

Above all, the lncRNA GAS5 regulates apoptosis and immune responses by inhibiting glucocorticoid receptor signaling and modulating the mTOR pathway [183]. Although reduced GAS5 expression has been observed in AA, suggesting impaired immune regulation that permits unchecked inflammation and subsequent follicular damage [183].

Furthermore, ANRIL plays a significant role in immune regulation [184]. By influencing CDKN2A and CDKN2B, genes involved in cell cycle control and senescence, ANRIL enhances inflammatory activity and contributes to follicular damage through the p53 pathway. Increased expression of ANRIL has been found in AA patients, underscoring its role in disease development [184, 185]. With continued research, targeting lncRNAs could offer a promising strategy for modulating immune responses in AA and ultimately improving patient outcomes. Identifying and targeting lncRNAs holds promise for advancing diagnostic accuracy and developing more precise therapies, paving the way toward personalized medicine in the management of AA. A summary of correlated studies is presented in Table 3.

Table 3.

lncRNAs regulatory role in Alopecia areata, melanoma, and cutaneous squamous cell carcinoma

lncRNAs	Diseases	lncRNA expression	Model	Target	Main findings	References
MIR17HG	Alopecia Areata	Up	Human peripheral blood/serum	miR-17-92a cluster	↑ MIR17HG/miR-17-92a cluster → linked to disease severity and autoimmune pathogenesis rs4284505 variant: A/G genotype → ↑ risk of AA; A/A genotype → protective miR-17: Potential diagnostic biomarker for AA with high sensitivity and specificity	[186]
NONHSAT011665, NONHSAT089844	Alopecia Areata	Up mixed	Human blood samples	ceRNA network (hsa-miR-186-5p/RPS26 axis)	154 differentially expressed lncRNAs (133 ↑, 21 ↓) identified in AA ↑ NONHSAT011665, NONHSAT089844 linked to AA progression via ceRNA regulation RPS26, SNX7, LRRC1 → high predictive accuracy for AA (ROC > 0.88)	[187]
AC005562.1, AF131217.1, RP11-251G23.5, RP11-231E19.1	Alopecia Areata	UP/Down	Human tissue	cytokine-cytokine receptor interaction, MAPK signaling, Ras signaling	166 differentially expressed lncRNAs (e.g., ↑ AC005562.1, AF131217.1, RP11-251G23.5; ↓ RP11-231E19.1) in AA RP11 lncRNAs, particularly RP11-251G23.5 and RP11-231E19, → AA pathogenesis, → potential therapeutic targets	[188]
NEAT1	Alopecia Areata	Down	Human blood	miR-101	↓ lncRNA NEAT1 in AA patients ↓ miR-101 → positive correlation with NEAT1 Diagnostic Biomarker: miR-101 showed 60% specificity and 75% sensitivity as a diagnostic marker for AA with a p-value = 0.001	[189]
HOTAIR	Alopecia Areata	Down	Human serum	miRNA-205/TGF-β1	↓ lncRNA-HOTAIR in AA patients (p < 0.001) ↑ miRNA-205, TGF-β1 in AA patients ↑miRNA-205, TGF-β1 and ↓ of HOTAIR → linked to AA, suggesting potential therapeutic targets	[190]
11 cis-regulated lncRNAs	Alopecia Areata	Up/Down	Human skin lesions	mRNA keratin family genes	116 differentially expressed lncRNAs identified, with 11 cis-regulated lncRNAs found to target 15 mRNAs 344 mRNAs differentially expressed → keratinization, ECD, IFO Keratin family genes identified as potentially key regulators in AA pathogenesis	[191]
FOXD2-AS1, others	Alopecia Areata	Up/Down	Human skin lesions	CD8A/miR-185-5p	26 DElncRNAs identified, including 9 upregulated lncRNAs located in the cytoplasm 173 DEGs → cytokines, chemokines, hair follicle development, and hair cycle signaling pathways CD8A, FOXD2-AS1, and miR-185-5p → potential regulatory network in AA pathogenesis CD8A and FOXD2-AS1 → diagnostic, therapeutic targets for AA	[181]
MEG3	Melanoma	Down	Human serum/plasma,body fluid	miR-208/SOX4	↓ lncRNAMEG3 → poor clinical outcomes ↑ MEG3 → inhibited proliferation, invasion, tumorigenesis, metastasis in melanoma cells MEG3 regulates miR-208, SOX4 → inhibiting miR-208 via SOX4 → suppressing melanoma progression MEG3 → tumor suppressor → potential therapeutic target for melanoma	[192]
CDR1as, LINC00632	Melanoma	Down	Human skin lesions, melanoma cell lines(A375,SK-MEL-28,WM793),mouse xenograft models	miR-7/IGF2BP3	↓ lncRNA CDR1as, upstream LINC00632 in melanoma CDR1as interacts with IGF2BP3 → invasion and metastasis Loss of CDR1as promotes melanoma metastasis → tumor suppressor, potential therapeutic target	[193]
8 immune-related lncRNAs	Melanoma	Variable	Human melanoma tumor transcriptome data from TCGA ana GEO databases	Immune cell infiltration (T cells CD8, M1 macrophages, etc.)	The risk score → independent prognostic factor for melanoma High-risk groups → ↓ T cells CD8, ↓ M1 macrophages, ↓ activated T cells CD4 memory, and other immune cells, while low-risk groups → ↓ macrophages M0 The immune-related lncRNA → prognostic markers and potential immunotherapeutic targets for melanoma	[194]
lincRNAs	Melanoma	Up	Human,cell lines	gene activation via CRISPR-Cas9	CRISPR-Cas9 complexes → transcriptional activation of EG activation of 10 genes and upregulation of lincRNAs Gene expression signatures → BRAF inhibitor resistance markers in cell lines and patient samples	[195]
NEAT1	Melanoma	Up	Mouse (B16F10 cells)	EMT (MMP-9, N-cadherin/E-cadherin)	↑ lncRNA NEAT1 → melanoma proliferation, migration, and invasion PPB → ↓ proliferation, migration, and invasion of melanoma cells in vitro and metastasis to lungs, bone, and liver in vivo PPB ↓ EMT-related proteins (e.g., MMP-9, N-cadherin) and ↑ E-cadherin, while ↑ NEAT1 reverses PPB’s inhibitory effects	[196]
8 pyroptosis-related lncRNAs	Melanoma	Variable	Human melanoma tumor transcriptome data from TCGA ana GEO databases	Immune status, TME	8 lncRNAs → prognostic risk model for CM Low-risk group → ↑ OS compared to the high-risk group The model offers better prognostic prediction and potential therapeutic targets for CM	[197]
AGAP2-AS1	Melanoma	Up	Human skin lesions, human melanoma cell lines(A375,A875), mouse xenograft model	SLC7A11/IGF2BP2 axis	↑ lncRNA AGAP2-AS1 → in melanoma tissues ↓AGAP2-AS1 → inhibited melanoma cell growth and promoted Erastin-mediated ferroptosis AGAP2-AS1 regulates SLC7A11 mRNA stability via the IGF2BP2 pathway, contributing to melanoma progression ↓AGAP2-AS1 → ↑Fe2 + levels and ↓GSH → promoting ferroptosis in melanoma cells	[198]
MSC-AS1	Melanoma	Up	Human (melanoma cell lines), Mouse (xenograft)	miR-330-3p/YAP1 axis	↑ lncRNA MSC-AS1 → in melanoma tissues and cells → poor prognosis MSC-AS1 → promoted YAP1 → ↓ miR-330-3p → timulating proliferation and glutaminolysis in melanoma cells ↓MSC-AS1 → inhibited proliferation and glutamine metabolism, while ↑YAP1 → reversed these effects	[199]
TME-related lncRNAs	Melanoma	Up/Down	Human melanoma transcriptome data	Immune cell infiltration, small-molecule drugs (W-13, AH-6809, Imatinib)	269 differentially expressed lncRNAs, with 69 ↑and 200↓ W-13, AH-6809, and Imatinib → potential small-molecule drugs for treating UM TME-related lncRNAs are critical in UM pathogenesis → biomarkers for diagnosis and treatment	[200]
MEG3	Melanoma	Up	Human tissue, cell lines, Mouse xenograft model	EMT	↑ lncRNA MEG3 → by GNA GNA → promoted EMT → inhibiting melanoma migration and metastasis GNA → inhibited melanoma progression in both cell culture and mouse models	[201]
FOXD3-AS1	Melanoma	Up	Human (A375, SK-MEL-1), Mouse (xenograft)	miR-325/MAP3K2 axis	↑ lncRNA FOXD3-AS1 → in melanoma tissues and cell lines ↓ FOXD3-AS1 → suppressed proliferation, migration, invasion, and tumor growth, and caused cell cycle arrest FOXD3-AS1 → ↓miR-325 → ↓expression FOXD3-AS1 → suppressing miR-325, promoting melanoma progression → ↑MAP3K2 levels	[202]
LENOX	Melanoma	Up	Human tissue, cell lines, Mouse xenograft model	RAP2C/DRP1 axis	↑LENOX → in melanoma cells LENOX → promoted RAP2C-DRP1 interaction → ↑DRP1 S637 phosphorylation → mitochondrial fusion → ↑OXPHOS ↓LENOX → MAPK inhibitors synergistically → eradicated melanoma cells LENOX → promising therapeutic target by disrupting mitochondrial function	[203]
RNCR2	Melanoma	Up	Human tissue, cell lines, Mouse xenograft model	miR-495-3p/HK2 axis	↑ lncRNA RNCR2 → in melanoma tissues and cell lines ↓ RNCR2 → inhibited proliferation, EMT, and glycolysis, while ↓ tumor growth in vivo RNCR2 → ↓ miR-495-3p RNCR2 → ↑HK2 → promoting glycolysis and tumor progression RNCR2 → ↑ melanoma growth in murine xenograft models RNCR2 → oncogenic biomarker and a potential therapeutic target for melanoma	[204]
NEAT1	Melanoma	Up	Human (A375 cells), Mouse (xenograft)	miR-495-3p/E2F3 axis	↑ lncRNA NEAT1 in melanoma cells → promoting proliferation, migration, and invasion NEAT1 → ↓ miR-495-3p levels → downregulated in melanoma cells NEAT1 → ↑E2F3 expression, the target of miR-495-3p → melanoma progression NEAT1 → oncogenic biomarker → potential therapeutic target in melanoma	[205]
PVT1	Melanoma	Up	Human(OCM-1)	EZH2	↑ lncRNA PVT1 in UM tissues compared to adjacent tissues (p < 0.05) ↓ PVT1 by siRNA inhibited UM cell proliferation (↓ colony formation) ↓PVT1 → ↑ apoptosis of UM cells ↓PVT1 → suppressed EZH2 protein expression → proliferation and apoptosis in UM cells	[206]
PICSAR, TINCR, LINC00520, LINC00319, THOR, AK144841, MALAT1, GAS5, LINC01048, HOTAIR	cSCC	Up/Down	Human skin lesions	MAPK/ERK, PI3K/AKT, Wnt/β-catenin signaling pathways, EMT	↑ PICSAR, LINC00319, THOR, AK144841, MALAT1, LINC01048, HOTAIR → in cSCC ↓TINCR, LINC00520, GAS5 → in cSCC Key pathways:MAPK/ERK, PI3K/AKT, and Wnt/β-catenin Several lncRNAs: HOTAIR, → regulated EMT → tumor progression Specific lncRNAs → biomarkers or therapeutic targets for cSCC	[207]
PICSAR, TINCR, LINC00520, LINC00319, THOR, MALAT1, GAS5, LINC01048, HOTAIR	cSCC	Up/Down	Human skin lesions	MAPK/ERK, PI3K/AKT, Hippo-YAP, EMT pathways	↑ PICSAR, LINC00319, THOR, MALAT1, LINC01048, HOTAIR → in cSCC → promoting proliferation, migration, invasion, and survival ↓TINCR, LINC00520, GAS5 → reduced differentiation, suppressed apoptosis, and tumor progression Dysregulated lncRNAs → biomarkers or therapeutic targets for cSCC	[208]
uc.291	cSCC	Down	Human skin lesions, cell lines(A431,HSC-5)	EDC (via ACTL6A/SWI-SNF axis)	uc.291 → in cSCC → contributing to tumor de-differentiation uc.291 interacts with ACTL6A → regulate the EDC genes, influencing chromatin accessibility ↓of uc.291 and BRG1 → promotes de-differentiation in keratinocyte malignancy Dysregulation of this axis could → biomarker cSCC and possibly other SCCs	[209]
NEAT1	cSCC	Up	Human skin tissue, Cell lines(A431, SCC13), Mouse (xenograft),	MMP-2, MMP-9, N-cadherin/E-cadherin, Vimentin	↑NEAT1 → CSCC tissues and → lymph node metastasis and TNM grade ↓NEAT1 → inhibited proliferation, migration, and invasion of CSCC cells ↓ MMP-2, ↓ MMP-9, ↓ N-cadherin, ↓ Vimentin (pro-metastatic markers),while ↑ E-cadherin (anti-metastatic marker)	[210]
HOTAIR	cSCC	Up	Human (A431, SCC13), Mouse (xenograft)	Sp1/DNMT1/miR-199a-5p axis	↑ lncRNAHOTAIR → CSCC tissues, cell lines, CSCSCs → OS HOTAIR → stemness, proliferation, sphere formation, and metastasis in CSCC in vitro and in vivo	[211]
NEAT1	cSCC	Up	Human (A431)	miR-342-3p/CUL4B/PI3K-Akt axis	↑ lncRNA → CSCC tissues and cell lines NEAT1 → ↓miR-342-3p → promoting proliferation and colony formation in CSCC cells NEAT1 → influenced the miR-342-3p/CUL4B/PI3K-Akt signaling pathway → ↑cell proliferation miR-342-3p mimics → inhibited proliferation, while miR-342-3p → ↑proliferation and colony formation in CSCC cells	[212]
TINCR	cSCC	Up	Human (A431)	ERK1/2-SP3 pathway, apoptosis, autophagy	↑ lncRNA TINCR → in CSCC A431 cells after ALA-PDT treatment ALA-PDT → ↑TINCR via the ERK1/2-SP3 pathway SP3 + TINCR promoter, → activate transcription TINCR → ALA-PDT therapy, → anti-cancer effects through apoptosis and autophagy induction	[213]
LINC00460	cSCC	Up	Human tissue, Mouse (xenograft)	ELAVL1/β-TrCP axis	↑ lncRNA LINC00460 → in CSCC tissues and cell lines ↓LINC00460 → inhibited proliferation, migration, invasion, and tumorigenesis in CSCC, both in vitro and in vivo LINC00460 + ELAVL1 → stabilizing it by preventing β-TrCP-mediated ubiquitination LINC00460, ELAVL1 → diagnostic markers and therapeutic targets for CSCC	[214]
GXYLT1P3, LINC00348, LOC101928131, A-33-p3340852, A-21-p0003442, LOC644838	cSCC	Up/Down	Human tissue	ACY3, NR1D1, MZB1 (endoplasmic reticulum stress, apoptosis, autophagy)	3593 lncRNAs and 3236 mRNAs were differentially expressed in CSCC lncRNAs → regulate ERS, apoptosis, and autophagy, contributing to cSCC progression	[215]
GAS5	cSCC	Down	Human tissue	miR-455-5p/CDKN1B axis	↓ lncRNA GAS5 → CCC) cells ↑GAS5 overexpression:↓ proliferation, migration, and invasion,↑ apoptosis in cSCC cells GAS5 + miR-455-5p → ↑CDKN1B GAS5 → tumor suppressor in cSCC → therapeutic target	[216]

-lncRNA: long non-coding RNA -AA: Alopecia Areata—MIR17HG: MiR-17-92a-1 Cluster Host Gene—ceRNA; Competing Endogenous RNA—hsa-miR-186-5p: Homo sapiens microRNA-186-5p—RPS26: Ribosomal Protein S26—SNX7: Sorting Nexin 7—LRRC1: Leucine Rich Repeat Containing 1—NEAT1: nuclear enriched abundant transcript 1—MAPK signaling: Mitogen-Activated Protein Kinase signaling—Ras signaling: Rat Sarcoma signaling—miR-101: microRNA-101—lncRNA-HOTAIR: Long noncoding RNA HOTAIR—TGF-β1: Transforming growth factor β1- mRNA: Messenger RNA—IFO: Intermediate filament organization—ECD: Epithelial cell differentiation—DEGs: Differentially expressed—CD8A: Cluster of Differentiation 8A—FOXD2-AS1: Forkhead Box D2 Antisense RNA 1—MEG3: Maternally Expressed Gene 3—miR-208: MicroRNA-208—SOX4: SRY-Box Transcription Factor 4—CD8 T cells: Cluster of Differentiation 8 T cells—CD4 T cells: Cluster of Differentiation 4 T cells—EG: Endogenous genes- lincRNA: long intergenic non-coding RNAs—CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats—Cas9: CRISPR-Associated Protein 9—BRAF: B-Raf Proto-Oncogene, Serine/Threonine Kinase—PPB: Polyphyllin B—EMT: Epithelial-Mesenchymal Transition—MMP-9: Matrix Metalloproteinase-9—N-cadherin: Neural-Cadherin—E-cadherin: Epithelial-Cadherin—CM: Cutaneous Melanoma—TME: Tumor Microenvironment—PVT1: Plasmacytoma Variant Translocation Gene 1—UM: Uveal Melanoma—UM: Uveal Melanoma—siRNA: Small Interfering RNA—OCM-1: Ocular Melanoma-1—miR-495-3p: microRNA-495-3p—E2F3: E2F Transcription Factor 3—OS: Overall Survival—RNCR2: Retinal Non-Coding RNA 2—HK2: Hexokinase 2—Long Intergenic Non-Coding RNA 00518—OXPHOS: Oxidative Phosphorylation—DRP1: Dynamin-Related Protein 1—RAP2C: RAS-Related Protein 2C—S637 phosphorylation: Phosphorylation of Serine 637 on DRP1—FOXD3-AS1: Forkhead Box D3 Antisense RNA 1—miR-325: MicroRNA-325—MAP3K2 Mitogen-Activated Protein Kinase Kinase Kinase 2—GNA: Gambogenic Acid—mir 330-3p: microRNA 330-3p—MSC-AS1: MSC Antisense RNA 1—YAP1: Yes-Associated Protein 1—AGAP2-AS1: AGAP2 Antisense RNA 1—SLC7A11: Solute Carrier Family 7 Member 11—IGF2BP2: Insulin-Like Growth Factor 2 mRNA-Binding Protein 2—GSH: Glutathione—cSCC: Cutaneous Squamous Cell Carcinoma—PICSAR: p38 Inhibited cSCC Associated lncRNA—TINCR: Terminal Differentiation-Induced Non-Coding RNA—LINC00520: Long Intergenic Non-Coding RNA 00520—LINC00319: Long Intergenic Non-Coding RNA 00319—THOR: Testis-Associated Highly Conserved Oncogenic RNA—AK144841: Novel lncRNA identified in cSCC—MALAT1: Metastasis-Associated Lung Adenocarcinoma Transcript 1—LINC01048: Long Intergenic Non-Coding RNA 01048—MAPK/ERK: Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase—PI3K/AKT: Phosphoinositide 3-Kinase/Protein Kinase B—GAS5: Growth Arrest-Specific 5—EDC: Epidermal differentiation complex—uc.291: Ultra-Conserved Region 291—ACTL6A: Actin-Like 6A—SWI/SNF: Switch/Sucrose Non-Fermenting Chromatin Remodeling Complex—BRG1: Brahma-Related Gene 1—MMP-2: Matrix Metalloproteinase-2—MMP-9: Matrix Metalloproteinase-9—TNM: Tumor, Node, Metastasis classification system—CSCSC: CSCC stem cells—Sp1: Specificity Protein 1—DNMT1: DNA Methyltransferase 1—HSFs: Human Skin Fibroblasts—miR-342-3p: MicroRNA-342-3p—CUL4B: Cullin 4B—ERK1/2: Extracellular Signal-Regulated Kinases 1 and 2—SP3: Specificity Protein 3—ALA-PDT: 5-Aminolevulinic Acid Photodynamic Therapy—LINC00460: Long Intergenic Noncoding RNA 460—ELAVL1: Embryonic Lethal Abnormal Vision-Like RNA Binding Protein 1—β-TrCP: Beta-Transducin Repeats-Containing Protein—ERS: endoplasmic reticulum stress—ACY3: Aminocyclase 3—NR1D1: Nuclear Receptor Subfamily 1 Group D Member 1—MZB1: Marginal Zone B and B1 Cell Specific Protein—miR-455-5p: MicroRNA-455-5p—CDKN1B: Cyclin-Dependent Kinase Inhibitor 1B

Melanoma

Melanoma is one of the most aggressive skin cancers, originating from melanocytes—the pigment-producing cells responsible for skin coloration and protection against ultraviolet (UV) radiation [217–219]. Although it represents only around 1% of all skin cancer cases, melanoma is the primary cause of skin cancer-related mortality due to its strong metastatic potential and resistance to conventional therapies [219]. Its incidence continues to rise globally, particularly among fair-skinned individuals with high UV exposure, making it a pressing public health concern [220]. Additionally, the disease arises through a multifaceted interaction of environmental, genetic, and host-related factors. A key ecological trigger is intermittent, intense UV radiation, which can induce sunburn and subsequent DNA damage in melanocytes, promoting malignant transformation [221].

Furthermore, in recent years, long non-coding RNAs (lncRNAs) have emerged as critical regulators in melanoma biology [222]. These RNA molecules, although not coding for proteins, influence gene expression and control multiple molecular pathways involved in tumor growth, invasion, immune evasion, and metastasis [222, 223].

For instance, MALAT1 promotes melanoma proliferation and invasion by engaging with the PI3K/AKT/mTOR and WNT/β-catenin signaling pathways. It acts as a competing endogenous RNA (ceRNA), sequestering tumor-suppressive miRNAs and thereby enhancing oncogenic signaling [224]. Another oncogenic lncRNA, SAMMSON, which is co-amplified with MITF and controlled by SOX10, is vital for the survival of melanoma cells. Besides, by interacting with p32, SAMMSON maintains mitochondrial homeostasis and metabolism. Inhibition of SAMMSON sensitizes melanoma cells to MAPK pathway inhibitors, making it a potential therapeutic target [225].

Furthermore, HAGLR promotes invasion and migration through the miR-4644/ASB11 axis [226]. HAGLR promotes melanoma cell invasiveness and facilitates immune evasion by downregulating miR-4644, upregulating ASB11, and modulating pathways such as JAK-STAT [226]. Similarly, KCNQ1OT1 facilitates melanoma growth through the miR-153/MET axis. Through suppression of miR-153, this lncRNA upregulates MET, the receptor for HGF, thereby amplifying PI3K/AKT and MAPK signaling to drive tumor growth and immune evasion [227]. In addition, DANCR (Differentiation Antagonizing Non-protein Coding RNA) promotes melanoma angiogenesis and progression through the miR-5194/VEGFB axis. Although silencing DANCR decreases VEGFB expression, thereby restricting tumor vascularization and limiting growth and activation of the VEGF pathway, it also reshapes the tumor microenvironment, enhances inflammatory responses, and weakens antitumor immunity [228, 229]. Another oncogenic lncRNA, MIR155HG, accelerates melanoma development via the miR-485-3p/PSIP1 axis, promoting proliferation and migration. Moreover, MIR155HG contributes to immune evasion by suppressing NF-κB signaling, a pathway crucial for antitumor immune activity [230].

Importantly, not all lncRNAs promote malignancy; some function as tumor suppressors [231]. MEG3 represents a prominent example, exerting inhibitory effects on melanoma progression by modulating the miR-208/SOX4 axis. By inhibiting miR-208, MEG3 enhances SOX4 expression, which counteracts metastasis. Moreover, MEG3 strengthens antitumor immunity by stimulating T cells and NK cells, thereby creating an immune-supportive tumor microenvironment [231]. Taken together, current evidence demonstrates that lncRNAs play a dual role in melanoma, acting either as oncogenic drivers that promote tumor progression or as suppressors that inhibit malignancy. Through their regulation of pivotal signaling cascades such as PI3K/AKT, MAPK, JAK-STAT, NF-κB, and VEGF, lncRNAs emerge as promising candidates for both diagnostic biomarkers and therapeutic intervention. Additional studies, summarized in Table 3, further highlight the breadth of their impact on melanoma biology.

Cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (CSCC) is a prevalent and increasingly diagnosed subtype of non-melanoma skin cancer (NMSC), arising from the malignant transformation of keratinocytes in the epidermis [232]. Its major risk factors include chronic ultraviolet (UV) exposure, immunosuppression, and genetic susceptibility. Besides, UV radiation, particularly from sunlight, induces DNA damage in keratinocytes, leading to mutations in regulatory genes and subsequent malignant transformation [232]. Although CSCC typically progresses slowly, it has the potential to invade surrounding tissue and metastasize in advanced stages, underscoring the importance of early detection and treatment [232]. Molecular mechanisms contributing to CSCC involve mutations in regulatory genes, in combination with environmental influences. Importantly, CSCC tumors often display a high mutational burden, especially in immunocompromised patients [233].

Furthermore, long non-coding RNAs (lncRNAs) have emerged as crucial regulators of gene expression in CSCC [234, 235]. These molecules exert their effects at multiple levels, including chromatin remodeling, transcriptional regulation, and post-transcriptional control of mRNA stability and translation. Acting as competitive endogenous RNAs (ceRNAs), lncRNAs sequester miRNAs from their target mRNAs, thereby influencing the expression of oncogenes and tumor suppressors critical for CSCC progression [234, 235].

Although several lncRNAs have been implicated in CSCC development through interactions with miRNAs and signaling pathways. For example, PICSAR and TINCR modulate cellular proliferation and differentiation by regulating the ERK1/2 signaling pathway [235]. Additionally, Zhao et al. demonstrated that in oral squamous cell carcinoma (OSCC), HCP5 functions as a molecular sponge for miR-140-5p, leading to the upregulation of SOX4—a regulatory mechanism also highly relevant to keratinocyte-derived tumors [236]. Similarly, within CSCC, HOTAIR has been reported to promote tumor progression through the miR-326/PRAF2 signaling axis [237]. More broadly, in the context of CSCC, a variety of lncRNAs are actively involved in the ceRNA network by sequestering miRNAs, such as miR-17-5p and miR-20b-5p. This competitive binding modulates the expression of crucial mRNAs, including CCND1 and E2F1, both of which serve indispensable functions in orchestrating cell cycle regulation and malignant proliferation [235].

Moreover, Mancini et al. found that in NMSC, which includes CSCC and basal cell carcinoma (BCC), the downregulation of lncRNA uc 291 and BRG1 caused the suppression of differentiation genes through ACTL6A. The study also highlighted a link between BRG1 expression and tumor grade, observing that poorly differentiated CSCCs had lower levels of BRG1 compared to well-differentiated tumors [209].

Among tumor-promoting lncRNAs, NEAT1 stands out as an essential contributor to CSCC development. Above all, studies demonstrated that NEAT1 silencing reduced the expression of EMT-associated markers, including N-cadherin, vimentin, MMP-2, and MMP-9, while simultaneously restoring E-cadherin levels. Silencing NEAT1 in CSCC cell lines (A431 and HSC-5) significantly reduced proliferation, colony formation, invasion, and migration. In vivo, silencing NEAT1 in a nude mouse xenograft model suppressed tumor growth, as evidenced by reduced tumor volume and weight, validating its oncogenic role in CSCC. These findings suggest that NEAT1 may serve as a valuable biomarker for diagnosis and prognosis, as well as a potential therapeutic target [210]. A summary of studies indicating the role of lncRNA in CSCC is provided in Table 3.

LncRNAs clinical implication in dermatological disorders

LncRNAs as diagnostic biomarkers in dermatologic disorders

Numerous studies have emphasized the significant role of lncRNAs in the diagnosis of various autoimmune disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), as well as different cancer types [238–244]. To illustrate, Guo et al. reported that lncRNA TCONS 00483150 interacts with several proteins, including HNRNPA1, FUS, and ELAVL1 [240]. Additionally, through these interactions, it exerts a regulatory influence on RNA maturation and cellular RNA dynamics, which ultimately affects gene expression patterns involved in inflammatory responses [240]. More importantly, using qRT-PCR, the study confirmed that this lncRNA is markedly downregulated in PBMCs from patients with SLE and RA. Notably, its reduced expression correlated with higher anti-Rib-P antibody titers and decreased complement C3 levels, thereby emphasizing its value as a potential biomarker for both conditions [240].

Furthermore, beyond autoimmune diseases, lncRNAs also hold considerable diagnostic promise in dermatologic disorders. For instance, in psoriasis, lncRNA MEG3 was shown to be markedly downregulated within lesional skin. Although its regulatory relationship with miR-21 influences keratinocyte proliferation and apoptosis, two processes central to psoriasis pathogenesis [245, 246]. Additionally, another lncRNA, MIR181A2HG, was also found to be reduced in psoriatic lesions. Acting as a molecular sponge for miR-223-3p, it impacts keratinocyte growth and thereby contributes to disease progression [247]. In contrast, upregulation of lncRNA NEAT1 has been associated with increased production of pro-inflammatory cytokines, particularly TNF-α, reinforcing its diagnostic potential in psoriatic disease [248].

Moreover, NEAT1 is also relevant in other immune-mediated disorders. Specifically, in BD, higher serum NEAT1 suggests a role in immune regulation through NGF-β silencing [160, 249]. In contrast, studies have reported decreased NEAT1 expression in BD plasma, with this reduction linked to higher IL-17 production mediated by miR-21 interactions [147]. Similarly, in AA, NEAT1 modulates immune imbalance through its interaction with miR-101 [189]. Additionally, in melanoma, NEAT1 inhibits miR-495-3p, leading to increased E2F3 expression. This upregulation enhances cell proliferation, migration, and invasion, contributing to tumor progression and highlighting its potential as a prognostic marker [205].

More importantly, vitiligo also involves lncRNA dysregulation. In this context, lncRNAs interact with SOD1 genes, influencing regulatory elements and transcription factors that drive abnormal protein differentiation and disease pathogenesis. Consequently, alterations in plasma SOD1 levels together with lncRNA activity may serve as diagnostic biomarkers [183]. Additionally, varying expression levels of LncRNAs, such as ENST00000460164.1 and NR_046211.1, in the PBMCs of patients with non-segmental Vitiligo (NSV) may also act as diagnostic indicators [250].

In SSc, Abd-Elmawla et al. reported elevated plasma expression of the lncRNAs SPRY4-IL1, HOTTIP, and TINCR. These were, respectively, associated with skin fibrosis, ANA positivity, and inflammatory activity, suggesting their involvement in disease mechanisms [166]. Conversely, decreased expression of ANCR correlated with fibrotic progression, underscoring its regulatory role in tissue remodeling and highlighting both upregulated and downregulated lncRNAs as potential biomarkers [166].

Furthermore, several lncRNAs, including ENST00000584157.1, ENST00000523380.1, and ENST00000560054.1, are differentially expressed in plasma exosomes of DM and participate in the regulation of autophagy networks [155]. Their dysregulation contributes to skeletal muscle damage and immune dysfunction by modulating key molecular pathways, including autophagy, interferon-beta (IFN-β) production, and mTOR signaling [155]. LncRNAs form ceRNA networks by interacting with miRNAs and mRNAs, thereby influencing immune-related pathways, including JAK/STAT. In DM, those linked to genes like C1orf106, COG8, and IFI6 show potential as biomarkers and therapeutic targets for predicting and managing CD4 + T-cell infiltration. [173, 251]. Considering that LINC00460 interacted with ELAVL1, inhibiting its ubiquitination through β-transducin repeats-containing protein (β-TrCP), promoting cell proliferation, migration, and invasion. Additionally, the elevated levels of LINC00460 in CSCC tissues and cell lines underscore its potential as a diagnostic biomarker [214]. Additional research linking the influence of lncRNAs in the diagnosis of dermatologic disorders is presented in Table 4.

Table 4.

LncRNAs as diagnostic biomarkers in dermatologic disorders

Targeted lncRNA and marker	Expression	Number of cases	Sample type	References
MEG3 miRNA-21	Down Up	Unknown	Psoriatic lesions, normal skin	[245]
NEAT1	Up	50 PP 50 HC	Blood of PP	[248]
MIR181A2HG	Down	Unknown	Psoriasis lesions tissue, HaCaT keratinocytes	[247]
10 differentially expressed lncRNAs	3 upregulated, 4 downregulated	Unknown	Psoriasis biopsies, HC samples	[252]
GAS5	Up	90 PP 90 HC	Circulating or cell-free lncRNA of PP	[253]
NEAT1	Up	Unknown	Serum of PP	[254]
LINC01137	Up	GSE13355 (skin biopsy samples of 180 cases), GSE30999 (skin biopsy samples of 170 cases) and GSE106992 (skin biopsy samples of 192 cases)	Skin tissue of PP	[255]
lncRNA SPRR2C	Up	11 PP 11 HC	CSCC tissue	[256]
lncRNA MIR31HG	Up	10	CSCC tissue	[257]
lncRNA PICSAR	Up	6 cSCC 7 normal skin	CSCC tissue	[258]
lncRNA EZR-AS1	Up	66 cSCC and healthy adjacent tissues	CSCC tissue	[259]
ncRNA LINC00162 (PICSAR)	Up	8 cSCC, 4 NHEK	CSCC cells and tissue	[260]
lncRNA HOTTIP,LINC00543	Up	Unknown	CSCC cells and tissue	[261]
lncRNA PVT1, LUCAT1, CASC9, circ_IFFO2, and circ_POF1B	Upregulated (PVT1, LUCAT1, CASC9) and downregulated (circ_IFFO2, circ_POF1B)	9 cSCC vs. 7 healthy skin	CSCC tissue	[262]
lncRNA PICSAR	Up	Unknown	CSCC serum and tissue	[263]
lncRNA NEAT1 and H19	Up	Unknown	CSCC tissue	[264]
LncRNA BASP1-AS1	Up	366	MP tissue	[265]
LncRNA SNHG15	Up	80	MP tissue	[266]
LncRNA NEAT1	Up	Unknown	MP cell lines and XNM model	[205]
LncRNA PRRT3-AS1	Up	Unknown	TCGA cohort and melanoma samples from GEO database	[267]
LncRNA MIR31HG	Up	Unknown	MP tissue and cell lines	[268]
ENST00000584157.1, ENST00000523380.1, ENST00000560054.1 (lncRNAs)	Up/Down	Unknown	EXOs from DM patients	[155]
3,835 lncRNAs in ceRNA network	Up/Down	Data from GSE46239, GSE142807, GSE1551, and GSE193276 datasets	Skin and muscle biopsy datasets from DM patients	[173]
miR-10a, miR-206, and other non-coding RNAs	Up/Down	Unknown	Muscle and potentially skin tissue samples from DM patients	[251]
multiple lncRNAs	Upregulated (32) and downregulated (78)	10 VP 10 HC	VP tissue	[139]
LncRNA MALAT-1	Up	20 VP 20 HC	VP tissue,serum	[141]
multiple lncRNAs	Upregulated (171) and downregulated (121)	5 VP 5 HC	PBMCs of VP	[250]
LncRNA NEAT1 and lnc-DC	NEAT1 (upregulated), lnc-DC (downregulated)	52 BD 52 HC	BD serum	[249]
LncRNA MEG3, lncRNA MAFG-AS1	Down	50 BD 50 HC	BD serum	[149]
MIAT, PVT1	MIAT (downregulated), PVT1 (upregulated)	70 BD 30 HC	BD serum	[148]
NEAT1	Down	Unknown	BD serum	[147]
NEAT1	Down	72 AA	AA serum	[189]
FOXD2-AS1	Up	Unknown	Gene expression data from GEO database (AA,HC)	[269]
multiple lncRNAs	Upregulated (8) and downregulated (3)	3 SSc	SSc tissue	[270]
LncRNA ANCR, TINCR, HOTTIP, SPRY4-IT1	ANCR (downregulated), TINCR, HOTTIP, and SPRY4-IT1 (upregulated)	63 SSc 35HC	SSc plasma	[166]
LncRNA ENST00000313807, NON-HSAT194388.1	up	Unknown	SSc CE	[182]

MEG3: Maternally Expressed Gene 3—miRNA-31: microRNA-21—NEAT1: nuclear enriched abundant transcript 1—LncRNA: long non-coding RNA—GAS5: Growth Arrest-Specific 5—PP: psoriasis patients—HC: healthy controls—HaCaT: Human Adult Low Calcium Temperature keratinocytes—LINC0113: Long Intergenic Non-Coding RNA 0113—SPRR2C: Small Proline-Rich Protein 2C—MIR31HG: MicroRNA 31 Host Gene—CSCC: cutaneous Squamous Cell Carcinoma—NHEK: normal human epidermal keratinocytes—PICSAR: p38 Inhibitor of Cancer-Associated Stromal Activation Regulator—EZR-AS1: Ezrin Antisense RNA 1—HOTTIP: HOXA Transcript at the Distal Tip—lncRNA PVT1: Long Non-Coding RNA Plasmacytoma Variant Translocation 1—LUCAT1: Lung Cancer Associated Transcript 1—LUCAT1: Lung Cancer Associated Transcript 1—circ_IFFO2: Circular RNA Intermediate Filament Family Orphan 2—circ_POF1B: Circular RNA Premature Ovarian Failure 1B—MP: melanoma patient—CE: Circulating exosomes—XNM: xenograft nude mice—EXOs: Plasma exosomes—DM: Dermatomyositis—VP: Vitiligo patients—BD: Behçet’s Disease—AA: Alopecia Areata—SSc: Systemic Sclerosis—LncRNA BASP1-AS1: Long non-coding RNA BASP1 Antisense RNA 1—LncRNA SNHG15: Long non-coding RNA Small Nucleolar RNA Host Gene 15—LncRNA PRRT3-AS1: Long non-coding RNA Proline Rich Transmembrane Protein 3 Antisense RNA 1—TCGA cohort: The Cancer Genome Atlas cohort—GEO: Gene Expression Omnibus—ceRNA: Competing Endogenous RNA—miR-10a: MicroRNA-10a—miR-206: MicroRNA-206—LncRNA MALAT-1: Long non-coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1—PBMCs: Peripheral Blood Mononuclear Cells—Lnc-DC: Long non-coding RNA Dendritic Cell—MAFG-AS1: MAFG Antisense RNA 1—MIAT: Myocardial Infarction Associated Transcript—FOXD2-AS1: Forkhead Box D2 Antisense RNA 1—LncRNA ANCR: Long non-coding RNA Anti-Differentiation Non-Coding RNA—LncRNA TINCR: Long non-coding RNA Terminal Differentiation-Induced Non-Coding RNA—LncRNA HOTTIP: Long non-coding RNA HOXA Transcript at the Distal Tip—LncRNA SPRY4-IT: Long non-coding RNA SPRY4 Intronic Transcript

LncRNAs as novel therapeutic targets in the treatment of dermatologic disorder

In recent years, accumulating evidence has highlighted the therapeutic and prognostic importance of long non-coding RNAs (lncRNAs) in autoimmune diseases as well as in various cancers [271–276]. For instance, Zhang et al. demonstrated that LEF1-AS1 plays a key role in rheumatoid arthritis (RA) by activating the PI3K/AKT pathway [277]. LncRNA LEF1-AS1 also acted as a sponge for miR-30-5p, precluding it from binding to and downregulating PIK3R2. This inhibition of PIK3R2 then triggered the activation of the PI3K/AKT signaling pathway, leading to excessive growth of synovial fibroblasts and elevated inflammation [277]. Additionally, the nano-drug delivery system (Zn-Adenine)@Ab@lncRNA LEF1-AS1 promoted the upregulation of LEF1-AS1, which subsequently increased PIK3R2 expression and reduced the activation of the PI3K/AKT pathway [277]. It was also revealed that silencing lncRNA NR_109 reduced the activity of M2-like macrophages, in contrast, leading to decreased tumor growth and metastasis via the NR_109/FUBP1/c-Myc pathway. Targeting this pathway could effectively hinder the pro-tumor functions of M2-like macrophages, presenting a potential new therapeutic target for cancer treatment [278].

Beyond autoimmune conditions, lncRNAs also represent promising therapeutic targets in dermatologic diseases, including CSCC, SSc, and melanoma. In CSCC, PICSAR enhances ERK1/2 activity by reducing DUSP6, a key inhibitor of this pathway, and this activation promotes tumor progression, indicating that restoring DUSP6 activity could be a viable therapeutic strategy [260]. Furthermore, PICSAR was shown to enhance resistance to the chemotherapy drug cisplatin (DDP) through the PICSAR/miR-485-5p/REV3L axis, whereby sequestration of miR-485-5p increased REV3L expression, thereby facilitating DNA repair and chemoresistance in CSCC cells [279].

In the study by Siena Á et al., the overexpression of lncRNA U73166 in metastatic melanoma cell lines underscored the potential of this lncRNA as a therapeutic target for melanoma progression and Vemurafenib resistance by MARK reactivation and PI3K/AKT activation. Vemurafenib, a BRAF inhibitor, promoted tumor growth by targeting BRAFV600E and activating the MARK/ERK pathway [280].

Additionally, lncRNAs such as ENST00000584157.1, which exhibited upregulation, and ENST00000523380.1/ENST00000560054.1, which demonstrated downregulation in DM patients, play a crucial role in the autophagy pathway [192]. Besides, these lncRNAs influenced disease progression by interacting with miRNAs such as hsa-miR-125a-3p, hsa-miR-1246, and hsa-miR-3614-5p and forming an autophagy network, regulating TGF-β and Wnt signaling pathways [155]. These lncRNAs affected the autophagy process in skeletal muscle myoblasts, potentially leading to muscle injury and noting them as a therapeutic target for DM treatment [155, 192]. Above all, lncRNA HOTAIR impacted the proliferation and apoptosis of hair follicles in AA through the lncRNA HOTAIR/miRNA-205/TGF-β signaling pathway, suggesting its therapeutic potential in AA treatment [190].

In SSc, TSIX was shown to be upregulated in fibroblasts, where it enhances collagen synthesis by stabilizing collagen mRNA through activation of endogenous TGF-β signaling. This mechanism contributes to collagen fiber deposition, thereby emphasizing TSIX as a potential therapeutic regulator [281].

Moreover, in psoriasis, MEG3 was found to be overexpressed in keratinocytes (HaCaT, NHEK) and in skin tissues from psoriatic mouse models. By inhibiting the PI3K/AKT/mTOR pathway, MEG3 overexpression reduced inflammation and enhanced autophagy in TNF-α–treated keratinocytes, highlighting its promise as a therapeutic target [282]. In addition, MEG3 regulates caspase-8 expression through the MEG3/miR-21 axis, thereby influencing keratinocyte proliferation and apoptosis. This mechanism provides an additional therapeutic strategy for controlling psoriasis progression [283].

Furthermore, in vitiligo, the interaction of FOXO3 with TUG1 promoted TUG1 overexpression and subsequent GATA3 upregulation via the miR-375 pathway. This process inhibited CD8 + T-cell migration and improved melanocyte survival, thus underscoring the therapeutic significance of TUG1 in vitiligo treatment [140].

More importantly, the lncRNA NEAT1 was confirmed to be downregulated in BD serum while conversely upregulating IL-17, a pro-inflammatory cytokine, and colchicine intake, suggesting the role of this lncRNA in the anti-inflammatory treatment of BD. In addition, NEAT1 downregulation and its negative correlation with IL-17 were shown to be associated with cyclophosphamide intake, a drug for severe BD manifestation [147]. Other studies correlated with a therapeutic target of lncRNAs in the treatment of dermatologic disorders are presented in Table 5.

Table 5.

LncRNAs as therapeutic targets in treatment of dermatologic disorder

Dermatologic disorder	LncRNAs	Expression	Treatment	Target/pathway	References
CSCC	PICSAR	Up	DDP	miR-485-5p/REV3L	[279]
CSCC	PVT1	Up	Targeting PVT1/4EBP1	PVT1/4EBP1	[284]
CSCC	LINC00319	Up	Gain-of-function, loss-of-function approaches	miR-1207-5p/CKD3	[285]
CSCC	Multiple ncRNAs (lncRNAs, miRNAs, circRNAs)	Up/Down	Diverse (chemotherapeutics, immune checkpoint inhibitors)	TC and PTC regulation	[286]
CSCC	THOC7-AS1	Up	THOC7-AS1 antisense oligonucleotides	THOC7-AS1/OCT1/FSTL1 axis	[287]
CSCC	SERLOC (BRD3OS/LINC00094)	Up	MEK1/ERK1/2 pathway inhibition	SE/MEK1/ERK1/2	[288]
CSCC	LINC00460	Up	LINC00460 knockdown	ELAVL1 stabilization by inhibiting β-TrCP-mediated ubiquitination	[214]
CSCC	PVT1	Up	CRISPR-Cas9-mediated knockout, LNA gapmer-mediated PVT1 knockdown	MYC/PVT1/p21/CDKN1A	[289]
CSCC	H19, miR-675	Up	H19 or miR-675 knockdown	miR-675/p53/EMT	[290]
CSCC	HCP5	Up	HCP5 overexpression, HCP5 knockdown, miR-138-5p mimics, miR-138-5p inhibitors	miR-138-5p/EZH2/STAT3/VEGFR2	[291]
Melanoma	MSC-AS1	Up	MSC-AS1 Knockdown	miR-330-3p/YAP1	[199]
Melanoma	8 TME-related lncRNAs	69 upregulated, 200 downregulated	W-13, AH-6809, Imatinib	TME immune cell infiltration, prognostic markers, gene expression regulation	[200]
Melanoma	RNCR2	Up	RNCR2 knockdown	miR-495-3p/HK2	[204]
Melanoma	JPX	Up	JPX knockdown	JPX/YTHDF2/USP10/BMP2/AKT	[292]
Melanoma	SLNCR1	Up	SLNCR1 knockdown	DNMT1/ SPRY2	[293]
Melanoma	MIR155HG	Up		miR-485-3p/PSIP1	[294]
Melanoma	6 differentially expressed lncRNAs	Up/down	EGFR inhibitor AG-490,Growth factor receptor inhibitor GW441756,Apoptosis stimulant betulinic acid	KEGG	[295]
Melanoma	HOXD-AS1	Up	HOXD-AS1 knockdown	HOXD-AS1/EZH2/RUNX3	[296]
Melanoma	18 Ferroptosis-related lncRNAs		Immunotherapy (targeting ferroptosis-related lncRNAs)	Ferroptosis-related genes (TP53, ACSL5, TF); immune infiltration;	[297]
Melanoma	PART1, LINC00968, LINC00954, LINC00944, LINC00518, C20orf197		anti-PD-1, anti-CTLA-4	Macrophage-associated immune processes	[298]
Melanoma	MALAT1	Up	si-MALAT1, miR-23a mimic	miR-23a	[299]
DM	ENST00000584157.1, ENST00000523380.1, ENST00000560054.1	UP/Down	Plasma EXOs, rapamycin, IFN-β stimulation	Autophagy, IFN-β production, mTOR signaling	[155]
DM	3,835 lncRNAs	UP/Down		CD4 + T-cell infiltration, JAK/STAT	[173]
Psoriasis	lnc-SPRR2G-2	Up	Gain-of-function, loss-of-function approaches	STAT3/KHSRP/mRNA decay of psoriasis-related cytokines	[300]
Psoriasis	PRINS	Down	Targeting RINS-miRNA-mRNA axis	miR-124-3p/miR-203a-5p/miR-129-5p/miR-146a-5p/miR-9-5p/NPM/G1P3	[301]
Psoriasis	GDA-1	Up	Gain-of-function, loss-of-function approaches	FOXM1/STAT3/NF-κB	[302]
Psoriasis	20-lncRNA signature	UP/Down	proteasome inhibitor therapy targeting the ubiquitination pathway	Proteasome/protein deubiquitination/ubiquitination-proteasome system	[303]
Psoriasis	AL035425.3, PWAR6	UP/Down	therapeutic targets based on the lncRNA-miRNA-mRNA ceRNA network	miRNA-associated ceRNA network/GO terms/KEGG pathways	[304]
Psoriasis	SPRR2C	Up	SPRR2C knockdown	miR-330/STAT1/S100A7	[305]
Psoriasis	BLACAT1	Up	BLACAT1 overexpression	miR-149-5p/AKT1	[306]
Psoriasis	MIR181A2HG	Down	MIR181A2HG knockdown	miR-223-3p/SOX6	[247]
Psoriasis	Snora73	Up	Snora73 Overexpression, Knockdown	miR-3074-5p/PBX1	[307]
Psoriasis	MSX2P1	Up	MSX2P1 downregulation	miR-6731-5p/S100A7	[308]
Vitiligo	Multiple	32 upregulated, 78 downregulated	RNA-Seq for profiling	lncRNA-mRNA network	[139]
Vitiligo	MALAT-1	Up	Targeting MALAT-1/ miR-9	MALAT-1/ miR-9	[141]
Vitiligo	LOC100506314	Up	Enhanced expression of LOC100506314	STAT3/MIF	[137]
Vitiligo	ENST00000460164.1, NR-046211.1	Up	lncRNA-miRNA-mRNA network	LncRNA-miRNA-mRNA network involving 2 lncRNAs, 17 miRNAs, and 223 mRNAs	[250]
Vitiligo	TUG1	Down	Upregulation of TUG1	miR-375/GATA3 axis, FOXO3-mediated regulation	[140]
Vitiligo	Mir17hg	Down	Overexpression or knockdown of Mir17hg	TGFβR2, TGFβ/SMAD signaling, PI3K/AKT/mTOR signaling	[138]
BD	MEG3, MAFG-AS1	Down	Targeting miRNA-147b/TLR signaling	miRNA-147b/TLR signaling	[149]
BD	NEAT1	Down	Colchicine, Cyclophosphamide	lncRNA-miRNA-mRNA Network	[147]
AA	FOXD2-AS1	Up	Targeting FOXD2-AS1/miR-185-5p/CD8A	FOXD2-AS1/miR-185-5p/CD8A	[269]
AA	HOTAIR	Down	Targeting HOTAIR/miRNA-205/TGF-β1	HOTAIR/miRNA-205/TGF-β1	[190]
AA	RP11-251G23.5,AC005562.1,AF131217.1;RP11-231E19.1	UpDown	Targeting lncRNA/cytokine-cytokine receptor interaction	lncRNA/cytokine-cytokine receptor interaction	[188]
SSc	Multiple	Dysregulated	Targeting IL-23, AMPK, NOTCH signaling pathways	IL-23, AMPK, NOTCH signaling pathways	[309]

TC: Transcriptional—PTC: post-transcriptional—CSCC: Cervical Squamous Cell Carcinoma—DDP: Cisplatin—miR-485-5p: MicroRNA 485-5p—PVT1: Plasmacytoma Variant Translocation 1—PICSAR: P38 Inhibited Cancer-Specific Apoptosis Regulator—4EBP1: Eukaryotic Translation Initiation Factor 4E-Binding Protein 1—LINC00319: Long Intergenic Non-Protein Coding RNA 319—miR-1207-5p: MicroRNA 1207-5p—CKD3: Cyclin-Dependent Kinase 3—lncRNA: Long Non-Coding RNA—miRNA: MicroRNA—circRNA: Circular RNA—THOC7-AS1: THO Complex Subunit 7 Antisense RNA 1—OCT1: Octamer-Binding Transcription Factor 1—FSTL1: Follistatin-Like 1—SERLOC: Small Evolving Region Locator—BRD3OS: BRD3 Opposite Strand—LINC00094: Long Intergenic Non-Protein Coding RNA 94—MEK1: MAPK/ERK kinase 1—ERK1/2: extracellular signal-regulated kinases 1 and 2 – LINC00460: Long Intergenic Non-Protein Coding RNA 460—ELAVL1: ELAV Like RNA Binding Protein 1—β-TrCP: Beta-Transducin Repeat Containing Protein—CRISPR-Cas9: Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-Associated Protein 9—LNA gapmer: Locked Nucleic Acid Gapmer—MYC: Myelocytomatosis Oncogene—CDKN1A: Cyclin-Dependent Kinase Inhibitor 1A—miR-675: MicroRNA 675—EMT: Epithelial-Mesenchymal Transition—HCP5: Human Endogenous Retrovirus Type-C Predisposing Element 5—miR-138-5p: MicroRNA 138-5p—EZH2: Enhancer of Zeste Homolog 2—STAT3: Signal Transducer and Activator of Transcription 3—VEGFR2: Vascular Endothelial Growth Factor Receptor 2—MSC-AS1: Mesenchymal Stem Cell Associated Transcript 1—miR-330-3p: MicroRNA 330-3p—YAP1: Yes-Associated Protein 1—TME-related LncRNAs: Tumor Microenvironment-Related Long Non-Coding RNAs—AH-6809: Prostaglandin E2 Receptor Antagonist—RNCR2: Retina-Specific Non-Coding RNA 2—JPX: Jpx Transcriptional Regulator RNA—SLNCR1: SRA-Like Non-Coding RNA 1—MIR155HG: MIR155 Host Gene—HOXD-AS1: HOXD Antisense RNA 1—miR-495-3p: MicroRNA 495-3p—HK2: Hexokinase 2—YTHDF2: YTH N6-Methyladenosine RNA Binding Protein 2—USP10: Ubiquitin Specific Peptidase 10—BMP2: Bone Morphogenetic Protein 2—DNMT1: DNA Methyltransferase 1—SPRY2: Sprouty RTK Signaling Antagonist 2—miR-485-3p: MicroRNA 485-3p—PSIP1: PC4 And SFRS1 Interacting Protein 1—KEGG: Kyoto Encyclopedia of Genes and Genomes—EGFR: Epidermal Growth Factor Receptor—RUNX3: Runt-Related Transcription Factor 3—TP53: Tumor Protein p53—ACSL5: Acyl-CoA Synthetase Long-Chain Family Member 5—TF: Transcription Factor—EXOs: Plasma exosomes—PART1: Prostate Androgen-Regulated Transcript 1—LINC00968: Long Intergenic Non-Protein Coding RNA 968—LINC00954: Long Intergenic Non-Protein Coding RNA 954—LINC00944: Long Intergenic Non-Protein Coding RNA 944—LINC00518: Long Intergenic Non-Protein Coding RNA 518—C20orf197: Chromosome 20 Open Reading Frame 197—anti-PD-1: Anti-Programmed Death-1—anti-CTLA-4: Anti-Cytotoxic T-Lymphocyte-Associated Protein 4—IFN-β: Interferon Beta—mTOR: Mechanistic Target of Rapamycin Signaling Pathway—JAK: Janus Kinase—STAT: Signal Transducer and Activator of Transcription—DM: Dermatomyositis—BD: Behçet’s Disease – AA: Alopecia Areata – SSc: Systemic Sclerosis – GO: Gene Oncology—PRINS: Psoriasis-Associated Non-Protein Coding RNA Induced by Stress—GDA-1: Growth Arrest-Specific DNA Damage Induced 1—PWAR6: Prostate Cancer Associated Long Non-Coding RNA 6—SPRR2C: Small Proline-Rich Protein 2C—BLACAT1: Bladder Cancer Associated Transcript 1—Snora73: Small Nucleolar RNA 73—KHSRP: KH-Type Splicing Regulatory Protein—miR-124-3p: MicroRNA 124-3p—miR-203a-5p: MicroRNA 203a-5p—miR-129-5p: MicroRNA 129-5p—miR-146a-5p: MicroRNA 146a-5p—miR-9-5p: MicroRNA 9-5p—NPM: Nucleophosmin—FOXM1: Forkhead Box M1—NF-κB: Nuclear Factor Kappa B—ceRNA: Competing Endogenous RNA—S100A7: S100 Calcium Binding Protein A7—miR-149-5p: MicroRNA 149-5p—AKT1: AKT Serine/Threonine Kinase 1—miR-223-3p: MicroRNA 223-3p—SOX6: SRY-Box Transcription Factor 6—miR-3074-5p: MicroRNA 3074-5p—PBX1: Pre-B-Cell Leukemia Homeobox 1—miR-6731-5p: MicroRNA 6731-5p—MALAT-1: Metastasis-Associated Lung Adenocarcinoma Transcript 1—MIF: Macrophage Migration Inhibitory Factor—TUG1: Taurine Upregulated Gene 1—Mir17hg: MIR17 Host Gene—MEG3: Maternally Expressed Gene 3—MAFG-AS1: MAFG Antisense RNA 1—NEAT1: Nuclear-Enriched Abundant Transcript 1—miR-185-5p: MicroRNA 185-5p—CD8A: Cluster of Differentiation 8 Alpha—miRNA-147b: MicroRNA 147b—TLR: Toll-Like Receptor—TGFβR2: Transforming Growth Factor Beta Receptor 2—TGFβ: Transforming Growth Factor Beta—SMAD signaling: SMAD Protein Signaling Pathway—PI3K: Phosphatidylinositol 3-Kinase—miRNA-205: MicroRNA 205—TGF-β1: Transforming Growth Factor Beta 1—IL-23: Interleukin 23—AMPK: AMP-Activated Protein Kinase

Conclusion

The field of lncRNAs has undergone remarkable progress in recent years, particularly in the context of genomics and dermatology, where these molecules are opening new opportunities for personalized therapeutic interventions. Noting their distinct structural features, wide diversity, tissue-specific expression, and complex regulatory functions, lncRNAs have emerged as particularly appealing therapeutic targets [1]. Importantly, the regulatory activity of lncRNAs is strongly tied to phenotypic outcomes that shift with the cellular context. This variability highlights the possibility of harnessing lncRNA modulation as a precise approach to disease management [1]. Consequently, research into lncRNAs in cutaneous biology and skin pathologies represents an expanding frontier of biomedical science. Nevertheless, only a limited fraction of lncRNAs have been functionally characterized in detail, leaving significant gaps in our knowledge regarding their biological roles and translational potential [1].

In this review, we underscore the significant dysregulation of lncRNA expression observed across a range of skin disorders; however, the field still faces a crucial limitation, namely the scarcity of functionally validated transcripts [39]. Moreover, realizing the full therapeutic potential of lncRNAs will require overcoming several key challenges. One major challenge lies in the incomplete understanding of their molecular biology, since much of our knowledge arises from studies of only a relatively small number of well-characterized lncRNAs [39]. Another major challenge is delivering unstable, negatively charged RNA molecules to specific locations, particularly solid tumors [310, 311]. Active research is underway to overcome these issues by improving delivery systems, including antibody-conjugated carriers and nanoparticle-based formulations, thereby expanding the accessibility of tumors to lncRNA-based therapies [312]. Moreover, progress in preclinical and clinical development has been hindered in part by the limited evolutionary conservation of lncRNAs, thereby making it challenging to evaluate safety and therapeutic effectiveness in standard non-primate models [313]. Nonetheless, efforts to leverage structural conservation to identify orthologs, combined with advances in organoid systems, hold promise for enhancing the precision and optimization of lncRNA-targeted therapies [314]. An equally critical step involves combining sequencing-based diagnostics with personalized therapeutic approaches. Because lncRNAs are detectable in body fluids using liquid biopsies, they serve as a minimally invasive tool for defining patient-specific molecular signatures. This strategy holds the potential to guide individualized treatments for dermatologic cancers and autoimmune disorders, thus bringing precision medicine closer to routine clinical practice [315, 316].

Strategies for targeting lncRNAs include transcriptional and post-transcriptional inhibition, interference with secondary structure formation, and the introduction of synthetic lncRNAs, with promising therapeutic loss-of-function (LOF) approaches utilizing siRNA-based drugs, antisense oligonucleotides (ASOs), and small molecule inhibitors [316, 317]. ASOs, particularly gapmers and steric blocker ASOs (SB-ASOs), are favored for their pharmacological properties and programmable design, with gapmers targeting nuclear lncRNAs and SB-ASOs allowing nuanced interventions [318, 319]. Small interfering RNAs (siRNAs) also show promise, utilizing the RNA-induced silencing complex (RISC) for RNA degradation, yet they face challenges in stability and delivery, often requiring lipid-like nanoparticles [320–323]. Small molecules can destabilize specific lncRNAs, and while they offer advantages in permeability, they also face challenges in optimization and understanding toxicity; ribonuclease-targeting chimeras (RIBOTACs) provide a solution for targeted RNA degradation [324]. Developing therapies for lncRNAs is complex yet promising, with ASOs, siRNAs, and small molecules presenting unique benefits and challenges. However, the field faces obstacles, including a lack of validation studies in cancer models, a limited understanding of their mechanisms, and a need for more specific inhibitors targeting lncRNAs.

In conclusion, this review provided valuable insights into skin-expressing lncRNAs and their involvement in various dermatological conditions, including atopic dermatitis, psoriasis, vitiligo, Behçet’s disease, systemic sclerosis, dermatomyositis, alopecia areata, melanoma, and cutaneous squamous cell carcinoma. Furthermore, it enhanced our understanding of the impact of lncRNAs on the clinical features of these diseases. This review is intended to serve as a valuable resource for advancing lncRNA research, particularly in the development of novel biomarkers and therapeutic strategies. A better understanding of their biological functions and improved targeting technologies is essential for advancing lncRNA treatment, with ongoing clinical trials focused on lncRNAs for cutaneous diseases.

Author contributions

A.Gh., S.N., and F.H. contributed to the hypothesis, investigating, gathering data, and writing the main text of the manuscript. M.T. and M.H. contributed to investigating, designing figures and table as well as content and grammatical editing. A.V. and S.T. contributed to the hypothesis, supervision, and verifying the final draft of manuscript before submission.

Funding

This research received no grant from any funding agency, commercial or not-for-profit sectors.

Data availability

Not applicable.

Declarations

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Conflict of interest

The authors declare that they have no conflict of interest.