The Crosstalk Between Non-Coding RNAs and Lipid Metabolism in Chronic Disease Progression

Abstract

In the last twenty years, an increasing volume of research has characterized lipids as dynamic signaling molecules that play essential roles in various physiological and pathological processes, especially concerning chronic diseases such as cardiovascular disorders, diabetes, liver disease, neurodegeneration, cancer, obesity, diabetic and chronic kidney diseases and atherosclerosis. Dysregulation of lipid synthesis and storage, lipolysis, fatty acid oxidation, lipid signaling pathways, and organelle-specific lipid modifications, including mitochondrial phospholipid remodeling and endoplasmic reticulum stress induced by saturated fatty acids, are recognized as contributors to the initiation and progression of this pathogenesis. Concurrently with the increasing comprehension of lipid metabolism, the last decade has seen progress in the understanding of genome control, especially with non-coding RNAs (ncRNAs). MicroRNAs, long non-coding RNAs, and circular RNAs, as ncRNAs, are essential modulators of gene expression at the epigenetic, transcriptional, and post-transcriptional levels that affect a number of lipid metabolism-related processes, such as fatty acid synthesis and oxidation, cholesterol homeostasis, and lipid droplet dynamics. Therapeutically, ncRNAs hold considerable promise owing to their tissue specificity and modularity, with antisense oligonucleotides and CRISPR-based editing currently under preclinical evaluation. In this context, we review recent studies exploring the interplay between ncRNAs and the regulatory networks governing lipid metabolism, and how disruptions in these networks contribute to chronic disease. This emerging paradigm underscores the role of ncRNA–lipid metabolism interactions as central nodes in metabolic and inflammatory pathways, highlighting the need for a holistic approach to therapeutic targeting.

1. Introduction

Lipid metabolism, the complex network of processes governing the synthesis, breakdown, and utilization of various lipids such as fatty acids, triglycerides, phospholipids, and cholesterol, is fundamental to cellular health, energy balance, and signaling [1]. Lipid metabolism has already been observed as operating in a confined manner, focused on the storage and release of energy, but is now widely perceived as a dynamic network that plays important roles in signaling, maintaining the integrity of cellular membranes, and systemic homeostasis [2,3]. Over the past two decades, an expanding body of research has redefined lipids as dynamic signaling molecules with critical roles in a variety of physiological and pathological processes, particularly in the context of chronic diseases [4,5]. Dysregulation of lipid metabolism contributes to a wide range of chronic diseases, including cardiovascular disorders, diabetes, liver disease, neurodegeneration, cancer, obesity, and atherosclerosis [6]. Dysregulation of lipid synthesis and storage, lipolysis, fatty acid oxidation, and lipid signaling pathways, are now known to be involved in the initiation and progression of such pathogenesis [7]. In the past, research concentrated on the classical pathways, i.e., fatty acid synthesis, β-oxidation, and cholesterol transport controlled by enzymes (i.e., acetyl-CoA carboxylase, HMG-CoA reductase) and by receptors (i.e., low-density lipoprotein (LDL) receptor) [8]. Nevertheless, progress in systems biology has revealed a more intricate landscape, where lipid metabolism intersects with inflammation, oxidative stress, and inter-organ crosstalk [9]. For example, lipotoxicity due to ectopic lipid deposition in non-adipose tissues causes insulin resistance generated by ceramides and diacylglycerols [10], and oxidized LDL particles exaggerate endothelial dysfunction in atherosclerosis [11]. Furthermore, organelle-specific lipid alterations, such as mitochondrial phospholipid re-modelling [12] or endoplasmic reticulum (ER) stress [13] derived from saturated fatty acids [14], are now believed to contribute to disease pathogenesis [15]. This new paradigm has highlighted lipid metabolism as a center for many metabolic and inflammatory pathways, necessitating a holistic approach to therapeutic targeting [16].

In parallel with the growing understanding of lipid metabolism, the past decade has witnessed advances in the understanding of genome regulation, particularly regarding non-coding RNAs (ncRNAs) [17]. MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as ncRNAs, are now recognized as crucial regulators of gene expression at the epigenetic, transcriptional, and post-transcriptional levels [18,19,20]. Studies have demonstrated that ncRNAs modulate various aspects of lipid metabolism, including fatty acid synthesis and oxidation, cholesterol homeostasis, and lipid droplet dynamics [21]. For example, specific miRNAs such as miR-33 and miR-122 have been shown to regulate cholesterol efflux and fatty acid metabolism, respectively [22]. LncRNAs, through diverse mechanisms involving chromatin remodeling, transcriptional interference, and miRNA sponging, also exert profound effects on lipid metabolic pathways [23]. lncRNA-LeXis modulates hepatic lipogenesis by sequestering the transcriptional coactivator Med1 [24], or lncRNA-ANRIL is associated with atherosclerosis risk [25]. CircRNAs add an additional layer of complexity by acting as molecular sponges for miRNAs, interacting with RNA-binding proteins, and potentially encoding functional peptides [26]. Beyond intracellular roles, ncRNAs mediate inter-organ communication via exosomes, e.g., adipocyte-derived miR-99b suppresses hepatic FGF21 expression, exacerbating metabolic syndrome [27]. Therapeutically, ncRNAs offer promise due to their tissue-specificity and modularity, with antisense oligonucleotides and CRISPR-based editing in preclinical testing [28]. However, challenges such as limited delivery efficiency and off-target effects persist [29]. In this regard, we summarize recent studies to understand the crosstalk between ncRNAs and the regulatory networks that control lipid metabolism, and how these networks become dysregulated in chronic disease.

2. Mechanisms and Dysregulation of Lipid Metabolism in Chronic Disease

The type and quantity of dietary lipids consumed are foundational determinants of cellular health and disease risk, impacting membrane composition and subsequent stability. An excess intake of saturated fatty acids can promote lipotoxicity and mitochondrial dysfunction, while the health benefits of polyunsaturated fatty acids (PUFAs), such as ω − 3 and ω − 6 families, stem from their critical role in maintaining the structure and fluidity of the phospholipid bilayer [30]. However, the high degree of unsaturation in PUFAs renders them uniquely vulnerable to lipid peroxidation, a degradative process initiated by reactive oxygen species (ROS). This results in the formation of numerous highly reactive PUFA metabolites, including malondialdehyde and 4-hydroxynonenal, which are potent electrophiles and signaling molecules [31]. These reactive PUFA metabolites inflict damage in two critical domains. First, they directly compromise the function of the cell bilayer by forming covalent adducts with membrane proteins and altering lipid packing, thereby disrupting membrane fluidity and essential signaling pathways [32]. Second, and more profoundly, these lipid-derived reactive species serve as endogenous genotoxic agents. Once they infiltrate the nucleus, they induce DNA damage through base modifications and the formation of DNA-adducts, significantly increasing the frequency of strand breaks and ultimately leading to genome instability [33,34]. Therefore, a complete understanding of lipid-associated diseases must encompass this pathway: from imbalanced dietary fat intake to membrane degradation, reactive metabolite generation, and the resultant threat to genomic integrity.

In chronic diseases, dysregulation of lipid pathways can contribute to lipotoxicity if excessive free fatty acids (FFAs) or cholesterol accumulate in tissues and impair function, as well as chronic inflammation that is driven by pro-inflammatory lipid mediators such as oxidized LDL or ceramides [35]. Mitochondrial dysfunction, ectopic lipid deposition, and dysregulated lipid signaling underscore the interconnectedness of chronic diseases. This paradigm serves to implicate lipid metabolism not as an afterthought of metabolism, but rather as a commanding orchestrator of chronic disease (Figure 1).

2.1. Cardiovascular Diseases

Atherosclerosis, the pathological cornerstone of cardiovascular disease (CVD), develops through lipid accumulation in arterial walls, where LDL cholesterol infiltrates the endothelial layer, triggering inflammation and initiating plaque formation [36]. Once LDL particles penetrate the arterial intima, they undergo oxidative modification, becoming oxidized LDL (oxLDL), which recruits macrophages that engulf these lipids, transforming into foam cells, a defining feature of atherosclerotic plaques. This process is exacerbated by lipid peroxidation, where ROS modify LDL, making it more atherogenic. The resulting oxLDL acts as a damage-associated molecular pattern (DAMP), binding to Toll-like receptor 4 (TLR4) on macrophages, which activates nuclear factor kappa B (NF-κB) signaling and induces the release of pro-inflammatory cytokines such as TNFα and IL-6, perpetuating vascular inflammation [37]. In contrast, high-density lipoprotein (HDL) exerts a protective role by facilitating reverse cholesterol transport, mobilizing excess cholesterol from peripheral tissues, including arterial lesions, to the liver for excretion [38,39]. However, dyslipidemia, characterized by elevated triglycerides (TGs) and lipoprotein A, exacerbates vascular damage [40]. Genetic predispositions, such as LDL receptor mutations that hinder LDL clearance [41], or dysregulation of lipid-modulating enzymes like lipoprotein lipase (essential for TG breakdown) [42] and cholesteryl ester transfer protein (CETP) (which mediates cholesterol exchange between lipoproteins) [43], amplify these risks. These genetic factors intersect with lifestyle choices, particularly diets high in saturated fats and sugars, to worsen lipid imbalances [44]. Therapeutic strategies aimed at reducing lipid accumulation and inflammation include weight loss to decrease lipid burden, drugs like proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors (for cholesterol management) [45], repurposing metabolic regulators (e.g., Peroxisome proliferator-activated receptors (PPAR-γ) agonists to enhance adipose lipid storage [46], ceramide synthesis inhibitors to reduce toxic lipid intermediates, TLR4 inhibitors to dampen inflammation, and antioxidants to mitigate oxidative stress and lipid peroxidation [47], offering potential avenues to mitigate CVD progression (Figure 1). This synergy between inherited susceptibilities and environmental influences underscores the complex gene-environment interplay driving CVD.

2.2. Obesity and Type 2 Diabetes

Obesity and type 2 diabetes mellitus (T2DM) are driven by a pathological interplay between ectopic lipid deposition and insulin resistance [48]. In obesity, dysfunctional adipose tissue becomes overwhelmed, leading to the spill-over of FFAs into non-adipose organs such as the liver, skeletal muscle, and pancreas [49]. This ectopic lipid accumulation triggers lipotoxicity, where lipid intermediates like diacylglycerol (DAG) and ceramides disrupt insulin signaling. DAG activates protein kinase C (PKC), impairing insulin receptor substrate (IRS) phosphorylation, while ceramides inhibit PI3K-Akt pathways, reducing glucose uptake and promoting insulin resistance (Figure 1) [50,51]. Additionally, ceramides activate the NLRP3 inflammasome, leading to the production of IL-1β, which further exacerbates insulin resistance and contributes to pancreatic β-cell dysfunction [52]. Lipotoxicity also induces mitochondrial dysfunction and ER stress, culminating in β-cell apoptosis and reduced insulin secretion [53,54]. Chronic nutrient overload overwhelms mitochondrial capacity, resulting in incomplete fatty acid oxidation and the accumulation of toxic lipid intermediates, which increase ROS production and oxidative stress, further impairing metabolic function [55,56]. Adipose-derived hormonal imbalances, such as leptin resistance and reduced adiponectin levels, promote hyperphagia and diminish insulin-sensitizing effects, while pro-inflammatory cytokines (e.g., TNFα, IL-6) fuel systemic inflammation, entrenching insulin resistance (Figure 1) [57,58]. The convergence of ectopic lipids, impaired insulin action, β-cell failure, and chronic inflammation creates a self-perpetuating metabolic crisis, underscoring the centrality of lipid dysregulation in obesity and T2DM pathogenesis.

2.3. Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD)

MASLD begins with hepatic steatosis, where excessive lipid accumulation arises from upregulated De Novo lipogenesis (DNL), the liver’s synthesis of new fats from carbohydrates, coupled with impaired fatty acid oxidation and defective secretion of very low-density lipoproteins (VLDL), which normally export triglycerides [59]. This ectopic lipid deposition, driven by Golgi and adipose tissue dysfunction and lipid overflow, leads to lipotoxicity, where toxic lipid intermediates like ceramides and cholesterol crystals activate inflammatory and fibrotic pathways [60,61]. Genetic variants, such as the PNPLA3 I148M (a common genetic variation that significantly increases the risk of MASLD), exacerbate lipid retention and oxidative stress by disrupting lipid droplet remodeling. Mitochondrial dysfunction further impairs fatty acid breakdown, resulting in incomplete oxidation and overproduction of ROS, which drive lipid peroxidation and hepatocyte damage [62,63,64]. Oxidative stress, combined with lipotoxicity from FFAs and cholesterol crystals, activates Kupffer cells and hepatic stellate cells, triggering inflammatory cytokines (e.g., TNFα, IL-6) and fibrotic pathways (e.g., TGF-β) (Figure 1) [65,66]. Specifically, cholesterol crystals stimulate the NLRP3 inflammasome, leading to IL-1β release and hepatocyte apoptosis [67], accelerating the progression from steatosis to Non-alcoholic steatohepatitis (NASH). These processes culminate in inflammation, hepatocyte ballooning, and fibrosis, potentially leading to cirrhosis or hepatocellular carcinoma (Figure 1) [68]. The interplay of metabolic overload, genetic predisposition, and oxidative damage underscores MASLD as a lipid-driven disorder with systemic metabolic implications.

2.4. Neurological Disorders

The brain’s lipid-rich composition, essential for myelination, synaptic plasticity, and neuronal signaling, makes it susceptible to lipid dysregulation, a key driver of neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s (PD) [69]. In AD, the apoE4 allele impairs cholesterol transport and lipid homeostasis, promoting amyloid-beta (Aβ) aggregation by reducing Aβ clearance and increasing plaque formation [70]. Sphingolipid imbalances, particularly ceramide accumulation, destabilize membrane microdomains (lipid rafts), altering amyloid precursor protein (APP) processing and enhancing neurotoxic Aβ production. Moreover, ceramides directly induce neuronal apoptosis and impair synaptic function, exacerbating cognitive decline [71,72]. Oxidative stress exacerbates phospholipid peroxidation, generating reactive aldehydes that damage neuronal membranes and organelles, while oxidized lipids in lipid rafts facilitate pathological Aβ-tau interactions, accelerating neurofibrillary tangle formation [73]. Additionally, oxidized lipids and Aβ peptides act as DAMPs and TLRs on microglia, which trigger NF-κB signaling and pro-inflammatory cytokine release, sustaining chronic neuroinflammation (Figure 1) [74]. In PD, lipid peroxidation products, such as oxidized dopamine derivatives and PUFAs, promote α-synuclein misfolding and aggregation into Lewy bodies, which disrupt synaptic function and cause dopaminergic neuron death. These processes are amplified by mitochondrial dysfunction and impaired antioxidant defenses, linking lipid peroxidation to oxidative damage and neuroinflammation [75,76]. These shared pathways of lipid dysregulation, oxidative stress, inflammation, and mitochondrial impairment highlight the potential for unified therapeutic strategies across neurodegenerative disorders.

2.5. Cancer

Cancer cells reprogram lipid metabolism to fuel uncontrolled growth, using lipids for structural components for membranes, signaling molecules, and energy sources [77]. Hyperactivation of sterol regulatory element-binding proteins (SREBPs), which reside in the ER, drives DNL, upregulating enzymes like fatty acid synthase (FASN) [78] and stearoyl-CoA desaturase-1 (SCD1) that synthesize and desaturate fatty acids, for lipid storage in lipid droplets for future energy needs [79]. These lipid droplets also buffer oxidative stress and support membrane synthesis during rapid proliferation [80,81,82]. Lipid signaling pathways, via bioactive lipids like sphingosine-1-phosphate (S1P) and Prostaglandin-Endoperoxide Synthase 2 (PTGS2), promote angiogenesis, metastasis, and immune suppression. PGE2, alongside the PI3K-Akt-mTOR axis, enhances tumor survival, growth, and resistance to apoptosis (Figure 1) [83]. Lipid-derived molecules like lysophosphatidic acid (LPA) and S1P activate pro-tumorigenic pathways, fostering immune evasion and metastatic spread [84]. Furthermore, lipid-laden tumor-associated macrophages (TAMs) adopt pro-tumorigenic phenotypes through TLR-driven pathways, supporting cancer progression and therapy resistance [85]. Cancer cells exhibit metabolic flexibility by scavenging exogenous lipids from the microenvironment, including adipocyte-derived fatty acids in breast cancer, to fuel growth [86] or lipid-rich extracellular vesicles from stromal cells [87]. This adaptability allows tumors to thrive under nutrient-poor conditions while evading therapies [88]. The interplay between intrinsic lipogenic reprogramming and microenvironmental lipid exploitation underscores lipid metabolism as a therapeutic vulnerability, with inhibitors targeting FASN, SREBPs, or lipid signaling pathways emerging as promising strategies to disrupt cancer progression (Figure 1).

3. NcRNAs as Regulators of Lipid Metabolism in Chronic Diseases

Recent high-throughput transcriptomic analyses have shown that up to 90% of eukaryotic genomic DNA is transcribed. However, only 1–2% of these transcripts encode proteins, while the vast majority are ncRNAs [89]. These RNAs are categorized by size and function: small ncRNAs such as miRNAs, which silence mRNAs via base-pairing; small interfering RNAs (siRNAs), involved in RNA interference [90]; and Piwi-interacting RNAs (piRNAs), which suppress transposons and lncRNAs, which scaffold chromatin modifiers (e.g., X-inactive specific transcript (XIST) in X-chromosome inactivation) or organize nuclear structures [91] and circRNAs, formed by back-splicing, act as miRNA sponges (e.g., CDR1as/miR-7) or modulate transcription (Figure 2) [92]. By interacting with DNA, RNA, proteins, or epigenetic machinery, ncRNAs fine-tune cellular homeostasis, development, and disease, with dysregulation linked to cancer, neurodegeneration, and cardiovascular disorders [93]. Their evolutionary conservation and clinical potential as biomarkers or therapeutic targets underscore their biological significance, redefining our understanding of genomic regulation beyond protein-coding genes.

3.1. MiRNAs

MiRNAs are small, conserved ncRNAs, transcribed as primary miRNAs (pri-miRNAs) and processed by Drosha-DGCR8 in the nucleus and Dicer in the cytoplasm into mature miRNAs [94,95]. They primarily regulate gene expression post-transcriptionally by incorporating into the RNA-induced silencing complex (RISC) and binding complementary sequences in the 3′ untranslated region (3′UTR) of target mRNAs, leading to translational repression or mRNA degradation [96]; for example, oncogenic miR-21 silences tumor suppressors like PTEN, promoting cancer progression [97,98,99]. A single miRNA can target hundreds of mRNAs, forming extensive regulatory networks essential for development, cell differentiation, proliferation, apoptosis, and metabolism [100]. Additionally, miRNAs influence epigenetic regulation by targeting enzymes like DNMT3B, a DNA methyltransferase; their downregulation in cancers leads to DNMT3B overexpression, causing hypermethylation of CpG islands in tumor suppressor gene promoters, silencing genes critical for cell cycle control and apoptosis, while miRNA-mediated suppression of DNMT3B can restore hypomethylation to reactivate these genes [101,102].

miRNAs critically regulate lipid metabolism by targeting multiple genes simultaneously [103]. They bind to mRNAs, repressing key enzymes (e.g., HMG-CoA reductase (HMGCR), FASN) [104], lipid transporters (e.g., ABCA1, CD36) [105,106], and transcription factors (e.g., PPARα, SREBP-1c) [107,108] involved in lipid synthesis, oxidation, and trafficking. In chronic diseases like atherosclerosis, T2D, MASLD, and AD, dysregulated miRNA expression disrupts lipid homeostasis, driving lipid accumulation, inflammation, and disease progression.

Table 1. MiRNAs involved in lipid metabolism.

miRNA	Target	Effect	Disease	References
miR-27b	HMGCR	Cholesterol synthesis	MASLD	[109,110]
miR-27a	Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)	Triglyceride accumulation, Adipogenesis	T2D, MASLD	[111,112]
miR-21	Secreted Frizzled-Related Protein 5 (SFRP5), vascular cell adhesion molecule 1 (VCAM-1), Peroxisome Proliferator-Activated Receptor Alpha (PPARα), PTEN/AKT signaling, TNFα, IL-6	Liver lipid-induced inflammation and fibrosis, decrease fatty acid oxidation, and increase lipid accumulation and Lipogenesis	MASLD/NASH, Atherosclerosis, T2D, DKD	[113,114,115,116,117,118,119,120]
miR-122	SREBP-1c, Carnitine palmitoyltransferase 1A (CPT1A), PPARα	Promotes DNL by targeting suppressors of lipogenesis, increases VLDL production, and causes hypertriglyceridemia	MASLD/NASH, T2D	[108,121,122,123]
miR-33a/b	CPT1A, ATP-binding cassette transporter A1 and G1 (ABCA1, ABCG1)	Represses fatty acid oxidation, reduces cholesterol, and Aβ efflux	Atherosclerosis, AD	[124,125,126,127]
miR-223	Scavenger Receptor Class B Type 1 (SCARB1 or SR-B1), ABCA1	Dysregulation of HDL cholesterol uptake and inflammation	Atherosclerosis, CVD, MASLD	[128,129,130,131]
miR-20a-5p	CD36	Lipid uptake and storage	MASLD, T2D, CVD	[132,133,134]
miR-34a	Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1), PPARα	Increases lipogenesis, less mitochondrial and peroxisomal fatty acid oxidation	MASLD/NASH, T2D, AD	[135,136,137,138]
miR-10b	PPARα, transforming growth factor beta 1 (TGF-β1)	Fatty acid oxidation and lipid accumulation	MASLD	[139,140]
miR-96	Adipose Triglyceride Lipase (ATGL), ABCA1, SREBP2	Represses intramuscular lipolysis, fatty acid oxidation, and uptake of HDL-associated cholesteryl esters	Atherosclerosis	[141,142,143]
miR-144	ABCA1	Decrease cholesterol efflux and HDL levels	Atherosclerosis	[144,145]
miR-155	ABCA1, Liver X Receptor α (LXRα)	Decrease cholesterol efflux and HDL formation	Atherosclerosis, T2D, AD	[146,147,148,149,150]
miR-29	HMGCR, SREBP-1c, Insulin Receptor Substrate 1 (IRS1), AKT3, PPARδ, GSK3β/SIRT1	Impairs insulin signaling, decreases fatty acid synthesis, and cholesterol production	MASLD/NASH, T2D, DKD	[151,152,153,154,155]
miR-143	oxysterol-binding protein-related protein 8 (ORP8), IRS1, MAP2K5–ERK5	Impairs insulin signaling, Adipogenesis	Atherosclerosis, T2D	[156,157,158]
miR-375	Adiponectin Receptor 2 (AdipoR2)	Decreases lipid oxidation	MASLD, T2D	[159,160,161]
miR-320	IRS1, CD36	Increase lipid accumulation	MASLD, T2D	[162,163]
miR-192	SREBF1, SCD1, PPARα	Increase lipid accumulation	MASLD/NASH, T2D	[164,165,166]
miR-106b	ABCA1, PTEN	Impairs cholesterol efflux	Atherosclerosis, AD, MASLD	[167,168,169]
miR-146a	Mediator complex subunit 1 (MED1), Tumor necrosis factor receptor-associated factor 6 (TRAF6)	Increase lipid accumulation	MASLD, AD, Atherosclerosis	[170,171,172,173]
miR-125	ELOVL fatty acid elongase 6 (Elovl6), NF-κB signaling, Sphingosine Kinase 1 (SphK1)	Increase lipid accumulation and inflammation	T2D, MASLD, AD	[174,175,176]
miR-137	AMP-activated protein kinase (AMPKα), Calcium channel subunit (CACNA1C), PTGS2	Decrease lipid accumulation, decrease inflammation,	MASLD, AD	[177,178]
miR-210	Insulin-like Growth Factor 2 (IGF2), Suppressor of Cytokine Signaling 1 (SOCS1)	Decrease lipid accumulation and inflammation,	Atherosclerosis, T2D	[179,180]
miR-124	Preadipocyte factor-1 (Pref1), SREBP2	Regulates triglyceride contents in hepatocytes, Lipid droplet formation	MASLD, Atherosclerosis	[181,182,183,184]
miR-130b	PPARγ, TNFα	Inflammation in adipose tissue and insulin sensitivity	Obesity, T2D	[185,186]
miR-126	SCARB1, hypoxia-inducible factor 1α (HIF1α)	Suppressing vascular inflammation	CVD	[187]
miR-148a	LDL receptors (LDLR), ABCA1	Regulates LDL-cholesterol uptake	Atherosclerosis	[188,189]
miR-103	Caveolin-1 (CAV1), SFRP4	Decreases adipocyte size and enhances insulin-stimulated glucose uptake	MASLD/NASH, T2D	[190,191]
miR-107	CAV1	Decreases adipocyte size and enhances insulin-stimulated glucose uptake	MASLD/NASH, T2D	[190]
miR-145	TNFα, NF-κB	Inflammation in adipose tissue	Obesity, Atherosclerosis	[192]
miR-7	LXR, ABCA1, 24-dehydrocholesterol reductase (DHCR24)	Regulates cholesterol efflux	AD, T2D	[193]

examines miRNAs as regulators of lipid metabolism and their specific roles in chronic diseases.

3.2. LncRNAs

LncRNAs are transcripts longer than 200 nucleotides, lacking significant open reading frames, and exhibit high sequence and structural diversity with tissue-specific and developmental stage-specific expression [194]. They regulate gene expression through multiple mechanisms: at the transcriptional level, lncRNAs can function as scaffolds for chromatin-modifying complexes such as Polycomb Repressive Complex 2 (PRC2) or interact with transcription factors and RNA polymerase II. For example, lncRNA-XIST recruits PRC2 to deposit repressive H3K27me3 marks, facilitating X-chromosome inactivation in females [195], while lncRNA-PANDA sequesters the transcription factor NF-YA to suppress pro-apoptotic gene expression during cellular stress responses [196]; post-transcriptionally, by modulating mRNA stability, translation, or splicing, such as lncRNA-NORAD, which binds PUMILIO proteins to stabilize pro-survival mRNAs during stress [197]; epigenetically, lncRNA-ANRIL promotes cancer by recruiting the PRC1 and PRC2 complexes to the INK4/ARF gene region, leading to the silencing of tumor suppressor genes such as p16^INK4a and p14^ARF through H3K27m3 and H2A ubiquitination [25,198]. Additionally, some lncRNAs regulate gene expression by acting as microRNA sponges, a mechanism known as competing endogenous RNA (ceRNA) activity. For example, lncRNA-H19 produces miR-675 and can also bind (sponge) it to protect the tumor suppressor RB (retinoblastoma protein). However, when lncRNA-H19 is overexpressed in cancer, excess miR-675 is released, which can suppress RB and contribute to tumor progression [199,200].

LncRNAs are pivotal regulators of lipid homeostasis, orchestrating lipid biosynthesis, storage, and signaling through transcriptional, post-transcriptional, and epigenetic mechanisms [201]. By interacting with RNA-binding proteins, miRNAs, or chromatin-modifying complexes, lncRNAs modulate key regulators like SREBP-1c, PPARs, and liver X receptors (LXR), balancing lipid synthesis and catabolism [202]. Dysregulation of lncRNAs disrupts this equilibrium, driving lipid accumulation, inflammation, and metabolic dysfunction in chronic diseases (

Table 2. LncRNAs involved in lipid metabolism.

lncRNA	Target	Effect	Disease	References
lnc-LeXis	RNA-binding protein RALY	Increases the hepatic cholesterol	MASLD/NASH	[204,205]
lnc-LSTR	TDP-43, Cyp8b1	Regulates bile acid composition, which influences lipid absorption and metabolism	Atherosclerosis	[206,207]
lnc-MALAT1	ABCA1, miRNA-17-5p, PPARα/CD36, miR-206, miR-382-3p	Inhibits glucose uptake and lipogenesis, increases cholesterol accumulation	Atherosclerosis, MASLD, T2D, DKD	[208,209,210,211,212]
lnc-H19	MLX-interacting protein-like (MLXIPL), mTORC1, PPARγ, miR-130b-3p	Increases lipid synthesis and accumulation, adipogenesis	MASLD, Atherosclerosis, DKD	[213,214,215]
lnc-ANRIL	Cyclin-dependent kinase inhibitor (CDKN2A/B), PRC1/2, NF-κB, ADIPOR1, VAMP3, C11ORF10	Impair cholesterol efflux, glycolipid metabolism	Atherosclerosis	[216,217,218,219]
lnc-BLNC1	Early B-cell factor 2 (EBF2), uncoupling protein 1 (UCP1), SREBP1c	Exacerbate insulin resistance, lipid accumulation, and adipogenesis	MASLD, T2D	[220,221,222]
lnc-MEG3	mir-21, Low-density lipoprotein receptor-related protein 6 (LRP6), Sirtuin 6 (SIRT6), FOXO1, Acetyl-CoA Carboxylase 1 (ACC1)	FFA-induced lipid accumulation	MASLD, T2D	[223,224,225,226]
lnc-LINC00473	UCP1, Cyclic adenosine monophosphate (cAMP), Perilipin 1 (PLIN1)	Lipolysis, respiration process, and mitochondrial oxidative metabolism	T2D	[227,228]
lnc-ADINR	c/EBPα, histone methyltransferase complex (MLL3/4), PA1	Adipogenesis	Obesity	[229,230]
lnc-NEAT1	ATGL, CCAAT/enhancer-binding protein α (CEBPα), PPARγ, miR-140, AMPK/SREBP-1 signaling, miR-146a-5p/ROCK1	Adipogenesis, lipolysis	MASLD, Atherosclerosis, AD	[231,232,233,234,235,236]
lnc-CHROME	miR-27b, miR-33a/b, miR-128, ABCA1	Cholesterol secretion and HDL synthesis,	Atherosclerosis	[237,238]
lnc-TUG1	miR-204/SIRT1, PPARα	Fatty acid β-oxidation	Obesity, T2D	[239,240,241]
lnc-Dnm3os	NF-κB, Nucleolin	Glucose uptake and increasing free fatty acid, inflammation-induced lipid accumulation	T2D	[242]
lnc-HI-LNC45	Unknown	β-cell dysfunction	T2D	[243,244]
lnc-SNHG1	Glutathione peroxidase 4 (GPX4), Nuclear factor erythroid 2-related factor 2 (NRF2), Nuclear Receptor Coactivator 4 (NCOA4), CD98, Polypyrimidine tract-binding protein 1 (PTBP1), miR-7/NLRP3,	Fatty acid β-oxidation, ferroptosis, adipogenic differentiation	PD	[245,246,247]
lnc-NRON	PER2/Rev-Erbα/FGF21, AMPK	Hepatic lipid homeostasis enhances adipose function via triacylglycerol hydrolysis	MASLD, T2D, Atherosclerosis	[248,249,250,251]
lnc-UCA1	PPARα, miR-30a-3p, retinoid X receptor α (RXRα), miR-143-3p, miR-214	Promotes lipid accumulation, mitochondrial dysfunction	T2D, MASLD, PD	[252,253,254,255]
lnc-MIAT (GOMAFU)	IL-1β, IL-6, and Tumor necrosis factor alpha (TNFα), HIF1α, FOXO1, miR-139-5p	Increases lipid content and reduces collagen content in the plaques, microvascular dysfunction, and promotes hepatic insulin resistance	Atherosclerosis, CVD, T2D	[256,257,258,259]
lnc-Gm15622	SREBP-1c, miR-742-3p	Lipid accumulation in hepatocytes	MASLD	[260]
lnc-HNF4A-AS1	Methyltransferase-like 3 (METTL3)	Regulates intracellular polyunsaturated fatty acids (PUFA)	MASLD	[261]

) [203]. Their roles as molecular scaffolds or signaling modulators position lncRNAs as critical players in disease pathogenesis and promising therapeutic targets or biomarkers.

3.3. CircRNAs

CircRNAs are covalently closed-loop structures formed by back-splicing of pre-mRNAs, comprising exons, introns, or both, and lack 5′ caps and 3′ tails, making them resistant to exonuclease degradation and highly stable. They regulate gene expression by acting as miRNA sponges, such as CDR1as (ciRS-7), which sequesters miR-7 to protect mRNA targets involved in brain development and neurodegeneration [262], or as protein scaffolds, like circFOXO3 (Forkhead box protein O3) which binds the E3 ubiquitin ligase MDM2 to stabilize the tumor suppressor FOXO3, enhancing stress resistance in cardiomyocytes [263]. Some circRNAs, like circEIF3J, bind RNA polymerase II at gene promoters to stabilize the transcription initiation complex and enhance host gene expression [264]. Emerging evidence suggests certain circRNAs can be translated into peptides via Internal Ribosome Entry Site (IRES) elements [265]. They are implicated in neuronal development, synaptic function, and cancer, with their stability and tissue-specific expression making them promising biomarkers.

CircRNAs are stable, covalently closed RNA molecules that regulate lipid metabolism and contribute to chronic diseases [266]. CircRNAs act as miRNA sponges, molecular scaffolds, and transcriptional regulators, modulating lipid enzymes, transporters, and gene expression [267]. By sequestering miRNAs, scaffolding proteins, or enhancing transcription, they fine-tune lipid biosynthesis, cholesterol efflux, and adipogenesis [268,269]. Dysregulation of circRNAs disrupts lipid homeostasis, promoting lipid accumulation, inflammation, and disease progression, making them promising biomarkers and therapeutic targets for lipid-driven pathologies (

Table 3. CircRNAs involved in lipid metabolism.

circRNA	Target	Effect	Disease	References
circRNA-0046367 circRNA-0046366	miR-34a/PPARα	β-oxidation of fatty acids	MASLD/NASH	[271,272,273]
circRNA-0001452 circRNA-0001453 circRNA-0001454	miR-466i-3p, miR-669c-3p, AMPK	Promotes the transcription and translation of lipogenic genes	MASLD	[274]
circRNA-0071410	miR-9-5p	Fibrosis development	MASLD/NASH	[272,275]
circRNA-SCD1	JAK2/STAT5	Hepatic lipid droplet formation	MASLD	[276,277]
circRNA-ABCA1	miR-140-3p/MAP2K6	Promotes cholesterol efflux to apolipoprotein A-I (apoA-I), β-oxidation of fatty acids	CVD, Atherosclerosis	[278,279,280]
circRNA-ANRIL	INK4/ARF, pescadillo homologue 1 (PES1)	Glycolipid metabolism, plaque growth	Atherosclerosis	[219,281,282,283]
circRNA-HIPK3	miR-192-5p, FOXO1, miR-190b, miR-106a-5p/MFN2	Effect of oleate on adipose deposition, Insulin resistance	Atherosclerosis, T2D, MASLD	[272,284,285,286,287]
circRNA-021412	miR-1972, Lipin 1 (LPN1)	Promotes liver steatosis and inflammation	MASLD	[288,289,290]
circRNA-SAMD4A	miR-138-5p/EZH2	Dysregulated adipogenesis and insulin signaling	Obesity	[291]
circRNA-LARP1B	cAMP/PKA signaling, Phosphodiesterase 4C (PDE4C)	Promotes lipid accumulation	Atherosclerosis	[292,293]
circRNA-ACC1	miR-338-3p, AMPK-ABCA1/ABCG1	β-oxidation of fatty acids	MASLD	[294,295]
circRNA-FUT10	let-7c/let-e, PPAR1β	Inhibit the differentiation of adipocytes	Obesity, T2D	[296]
circRNA-0000660	miR-693, Insulin-like Growth Factor Binding Protein 1 (IGFbp1)	Liver lipid accumulation	Obesity	[297]
circRNA-0003546	miR-326, PDE3B	Increases Lipid efflux	Atherosclerosis	[298]
circRNA-0092317	miR-543, miR-326, PDE3B	Increases Lipid efflux	Atherosclerosis	[298]
circRNA-ARF3	miR-103, TNF receptor-associated factor 3 (TRAF3)	Inflammation in adipose tissue	Obesity	[299]

) [270].

3.4. Other Subclasses of ncRNAs

Beyond miRNAs, lncRNAs, and circRNAs, several specialized ncRNA subclasses contribute to gene regulation. Small nucleolar RNAs (snoRNAs) guide site-specific chemical modifications, such as 2′-O-methylation and pseudouridylation, in ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs), ensuring proper ribosome assembly, with dysregulation linked to ribosomopathies like Prader–Willi syndrome [300]. PiRNAs, slightly longer than miRNAs, partner with PIWI-clade Argonaute proteins to silence transposable elements in germline cells, securing genomic stability and fertility through epigenetic regulation, with aberrant expression implicated in cancers and infertility [301,302]. snRNAs, such as U1 and U2, are core spliceosome components, directing precise intron removal during pre-mRNA splicing to generate mature transcripts [303]. Enhancer RNAs (eRNAs), transcribed from active enhancer regions, promote chromatin looping or recruit transcriptional coactivators like the Mediator complex to amplify target gene expression, influencing cell identity and disease states like cancer [304]. These subclasses fine-tune RNA processing, genome defense, and transcriptional activation, collectively shaping cellular function and adaptability, with dysregulation contributing to chronic diseases like cancer and infertility.

4. NcRNA-Lipid Interaction Networks Across Organ Systems

NcRNAs form multi-tiered interaction networks that maintain systemic lipid homeostasis. These networks operate inter-organically, enabling crosstalk between the liver, adipose tissue, brain, and vasculature [305], while intra-organically fine-tuning tissue-specific responses by intersecting with inflammatory and oxidative stress pathways [306]. This integration allows ncRNAs to synchronize metabolic flux, inflammation, and redox signaling across organs, thereby preserving physiological equilibrium or, upon dysregulation, propagating diseases like MASLD, obesity, and cardiovascular disorders through amplified lipotoxicity and impaired lipid trafficking [220,307].

Systemic lipid crosstalk relies on circulating ncRNA–lipid complexes, where ncRNAs, primarily miRNAs, are trafficked via extracellular vesicles (EVs) (e.g., exosomes, microvesicles) or directly bound to lipoproteins (e.g., HDL), acting as endocrine messengers that transmit metabolic signals across organs [308,309]. Hepatocyte-derived EVs, enriched in miRNAs like miR-122 (constituting 70% of hepatic miRNAs) and miR-192, are internalized by adipocytes to suppress PPARα and AdipoR1, reducing lipid oxidation and altering adipokine secretion (e.g., adiponectin, leptin) [122,310,311], while adipose tissue releases EVs carrying miR-27 or miR-130b to inhibit hepatic PPARγ, curbing lipogenesis and VLDL assembly, establishing a bidirectional liver-adipose axis [312]. Beyond EVs, lipoprotein-ncRNA complexes exhibit cargo specificity: HDL transports miR-223 and miR-126 to endothelial cells, promoting ABCA1/G1-mediated cholesterol efflux and suppressing vascular inflammation [131,187], whereas LDL-bound miR-148a enhances lipid uptake by targeting LDLR [189]. Dysregulation of this network illustrates how ncRNA-lipid shuttling synchronizes inter-organ metabolism but propagates disease when disrupted.

4.1. Liver

The liver orchestrates lipid homeostasis through hierarchically organized ncRNA networks that precisely control synthesis, oxidation, and lipoprotein export [313]. MiRNAs like miR-33a/b (embedded in SREBP2/1 introns) suppress ABCA1 and ABCG1 to limit cholesterol efflux, simultaneously inhibiting CPT1A and HADHB to repress fatty acid β-oxidation, thereby promoting lipid retention [125,126,127]. LncRNAs exert epigenetic control: HNF4A-AS1 binds to METTL3, promoting m6A modification of DECR1 mRNA. This modification facilitates YTHDF3-mediated degradation of DECR1, reducing its expression. When HNF4A-AS1 is downregulated, DECR1 expression increases, which lowers intracellular PUFA levels and confers resistance to sorafenib-triggered ferroptosis in hepatocellular carcinoma [261,314]. The downregulation of MEG3 in vitro and vivo models of MASLD showed a negative correlation with lipogenesis-related genes [226]. CircRNAs fine-tune these networks via competitive sponging; circRNA_0046367 (downregulated in steatosis) adsorbs miR-34a, preventing its repression of SIRT1 and PPARα, thereby boosting β-oxidation of fatty acids (Figure 3) [205].

4.2. Adipose Tissue

Adipose tissue employs a sophisticated ncRNA regulatory framework to govern adipogenesis, lipid storage dynamics, and systemic metabolic crosstalk (Figure 4) [315]. MiRNAs such as miR-143 regulate adipogenesis by modulating the MAP2K5-ERK5 signaling [156]. In adipocytes, suppression of miR-103/107 leads to increased caveolin-1 expression, which stabilizes the insulin receptor, enhances insulin signaling, reduces adipocyte size, and improves insulin-stimulated glucose uptake. These results highlight the critical role of miR-103/107 in regulating insulin sensitivity and suggest a potential therapeutic target for type 2 diabetes and obesity [190,191]. MiR-145 promotes TNF-α production, and it induces inflammation by activating NF-κB in human adipose tissue [192]. LncRNAs orchestrate chromatin remodeling: lncRNA-ADINR plays an important role in regulating the differentiation of human mesenchymal stem cells into adipocytes by modulating C/EBPα. ADINR regulates the differentiation of human mesenchymal stem cells into adipocytes by controlling C/EBPα expression in a cis-acting manner [230]. On the other hand, lncRNA-Blnc1 enhances thermogenic gene activation in brown adipocytes by assembling a ribonucleoprotein complex with hnRNPU and EBF2 [221]. CircARF3 acts as a sponge for miR-103, relieving its inhibition on TRAF3 and thereby increasing TRAF3 expression. Through this mechanism, circARF3 promotes mitophagy and reduces inflammation in adipose tissue [299]. Crucially, adipose-derived exosomal ncRNAs mediate inter-organ signaling, obese adipocytes release exosomes enriched in miR-27a (targeting hepatic PPARγ), and miR-27a secreted into circulation by adipose tissue may regulate insulin resistance in skeletal muscle [111]. MiR-130b suppresses PPARγ, thereby influencing macrophage polarization, promoting adipose tissue inflammation, and impairing insulin sensitivity [186]. Dysregulation in obesity triggers pathogenic feedback loops; the expression of miR-155 plays a role in the link between adipose tissue dysfunction and the development of obesity associated disorders, including T2D [186]. This ncRNA-driven dysfunction promotes ectopic lipid deposition, insulin resistance, and meta-inflammation, positioning adipose ncRNAs as both biomarkers and therapeutic targets for metabolic syndrome.

4.3. Brain

The brain holds nearly 25% of the body’s total cholesterol, with about 70–80% localized in myelin, where it plays an essential role in insulation [316]. MiRNAs such as miR-33 overexpression disrupts cholesterol efflux and elevates extracellular Aβ levels by enhancing its secretion and reducing its clearance in neural cells [124]. MiR-124 regulates SREBP2 levels and lipid droplet formation in microglia [184]. Knockdown of lncRNA-NEAT1 prevents post-stroke lipid droplet agglomeration in microglia by regulating autophagy [236]. MiR-155/MafB axis also contributes to dyslipidemia and atherosclerosis in cerebrovascular disease, which is one of the AD-related modifiable risk factors [150]. MiR-7 controls cholesterol biosynthesis through posttranscriptional regulation of DHCR24 expression in AD [193]. These disruptions position ncRNA–lipid crosstalk as a pivotal axis in neurodegenerative pathogenesis and a potential biomarker/therapeutic target (Figure 5).

4.4. Vasculature

NcRNA networks act in a cell-type-dependent manner within the vasculature, where endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) rely on different ncRNA sets to regulate lipid metabolism, preserve barrier function, and control inflammation, thereby maintaining vascular protection while counteracting atherosclerosis (Figure 6) [317]. Endothelial miRNA, like miR-223-3p, modulates cholesterol metabolism through directly or indirectly targeting genes related to cholesterol transport, biosynthesis, and efflux. Both HDL-carried miR-223-3p and hepatocyte-expressed miR-223-3p could execute the regulatory function. MiR-223-3p could inhibit the expression of SR-BI, while the inhibition could lead to reduced uptake of HDL-carried miR-223-3p from plasma, so this loop regulation may be one of the mechanisms helping to maintain the cholesterol homeostasis at the cellular or systemic level [129]. Diet-induced hypercholesterolaemia alters the miRNA composition of HDL, resulting in increased levels of miR-126, which can be transferred to ECs and disrupt essential vascular processes [187]. In VSMCs, MiR-145-5p modulated lipid metabolism and M2 macrophage polarization by targeting PAK7 and regulating β-catenin signaling in hyperlipidemia, which may provide a potential biomarker for the treatment of hyperlipidemia-induced cardiovascular diseases [318]. LncRNA-H19 induces lipid metabolic disorders in foam cells by suppressing lipid metabolism and increasing lipid accumulation, which contribute to the progression of atherosclerosis and participate in vascular physiopathology and angiogenesis [215]. Moreover, lncRNA-ANRIL modulates vascular endothelial function and affects macrophage cholesterol handling, linking it to both atherosclerosis progression and impaired lipid metabolism [216]. CircRNA-ABCA1 is up-regulated in atherosclerotic aortic vessels and H₂O₂-treated ECs. It has potential regulatory effects on atherosclerosis and vascular endothelial injury by targeting miR-30d-3p-TP53RK and miR-140-3p-MKK6 axis and their downstream signaling pathways [279]. CircRNA-ABCA1 promoted cholesterol biosynthesis by regulating miR-140-3p/HMGCR and HMGCS1 axis. It is worth mentioning that ABCA1 promotes cholesterol efflux to apolipoprotein A-I (apoA-I) to suppress foam cell formation [278].

4.5. Kidney

Recent studies have highlighted that ncRNAs are not only involved in hepatic or vascular lipid dysfunction but also play central roles in renal injury associated with metabolic disorders. For instance, miR-21 is upregulated in diabetic nephropathy (DN), and its silencing ameliorates mesangial expansion, interstitial fibrosis, podocyte loss, inflammatory gene expression, and albuminuria in diabetic mouse models [319]. In human patients, serum miR-21 correlates with structural and functional markers of DN (e.g., GBM thickening, albumin-creatinine ratio) [320]. Another miRNA, miR-29b, shows increased urinary levels in early Diabetic kidney disease (DKD) and is negatively associated with renal function. Its overexpression exacerbates podocyte injury via suppression of mitochondrial biogenesis regulator PGC-1α, while inhibition of miR-29b preserves podocyte integrity in mouse DKD models [321]. On the lncRNA side, MALAT1 is significantly upregulated in peripheral blood mononuclear cells of DKD patients and correlates with albuminuria, urinary β₂- and α₁-microglobulin, creatinine, and HbA1c [322]. In renal tubular epithelial cells under high glucose, MALAT1 promotes injury via interactions with LIN28A and Nox4, affecting the AMPK/mTOR pathway. Its knockdown reduces apoptosis, reactive oxygen species, and inflammatory cytokine secretion [323]. LncRNA-p21 is induced in renal tubule cells under lipotoxic conditions (high-fat diet or palmitic acid exposure), its tubule-specific deletion reduces oxidative stress, inflammation, apoptosis, and histologic kidney injury despite ongoing hyperlipidemia [324]. LncRNA H19, alleviates renal tubulointerstitial fibrosis via reducing lipid accumulation and triglyceride content through modulating the miR-130a-3p/ACSL1 axis in mouse kidneys and in vitro [325]. These examples together strengthen the argument that lipid-metabolic dysregulation mediated by ncRNAs plays a substantial role in DKD and chronic kidney disease pathogenesis and offers both mechanistic insight and potential biomarkers/therapeutic targets (Figure 7).

4.6. Cross-Study Comparative Analysis of ncRNA–Lipid Associations Across Organ Systems

A cross-study comparison highlights that a set of ncRNAs recur across cardiovascular, metabolic, and hepatic diseases and that these molecules often converge on a few shared lipid-handling hubs. In CVDs, the association between lipids and ncRNAs manifests prominently through dysregulated cholesterol homeostasis and inflammatory signaling. For instance, miR-33a/b targets ABCA1 and ABCG1 to inhibit cholesterol efflux, promoting foam cell formation and plaque progression in atherosclerosis [22,126,127]. Similarly, lncRNA-MALAT1 exacerbates lipid accumulation by sponging miR-206, leading to endothelial dysfunction and vascular inflammation [212]. In contrast, hepatic disorders like MASLD show overlapping yet distinct cross-talk, where miR-122 enhances DNL by suppressing PPARα, resulting in triglyceride buildup and steatosis [22,121,122,123]. Cross-comparisons reveal that while CVD studies emphasize oxLDL-driven ncRNA alterations (e.g., miR-155 inhibiting ABCA1) [148,211], hepatic research highlights FFA-induced endoplasmic reticulum stress modulating ncRNAs like lnc-MEG3, which reduces lipid accumulation via SIRT6/FOXO1 pathways [223,225]. This suggests a shared inflammatory lipid mediator role, such as ceramides, but with tissue-specific outcomes: vascular plaque instability in CVD versus hepatocyte ballooning in MASLD.

Metabolic changes in obesity and T2D underscore the lipids-ncRNAs interplay through insulin resistance and ectopic lipid deposition, often compared to hepatic pathologies for their interconnected pathways. miR-27a targets PPARγ to promote triglyceride accumulation in adipocytes [111], mirroring its role in hepatic DNL upregulation in MASLD models [112] where it correlates with increased VLDL secretion and hypertriglyceridemia. LncRNA-BLNC1, by enhancing SREBP1c activity, drives adipogenesis and insulin resistance in obese tissues, a mechanism echoed in diabetic hepatic steatosis via similar SREBP-mediated lipogenesis [122]. However, cross-study analyses highlight divergences: metabolic-focused research, such as in high-fat diet, links ceramide accumulation to ncRNA dysregulation (e.g., miR-34a inhibiting PPARα and leads to less mitochondrial and peroxisomal fatty acid oxidation), fostering systemic inflammation [52,136], whereas hepatic studies emphasize cholesterol crystal activation of NLRP3 inflammasomes via ncRNAs like circRNA-0046367 [60,61,67,205]. This cross-talk convergence points to exosomal ncRNA transfer (e.g., adipocyte-derived miR-130b suppressing hepatic PPARγ) [186,308,312], amplifying metabolic-hepatic feedback loops, yet metabolic disorders exhibit broader inter-organ effects compared to localized hepatic fibrosis.

Neurological disorders, such as AD, reveal a unique lipids-ncRNAs association centered on sphingolipid imbalances and oxidative stress, providing a comparative lens to cardiovascular and metabolic pathologies [71,72,73]. MiR-33a/b, implicated in CVD for repressing fatty acid oxidation, similarly reduces Aβ efflux in AD by targeting ABCA1, leading to amyloid plaque formation akin to atherosclerotic plaques [124,125,126]. LncRNA-NEAT1 modulates lipid droplet dynamics in microglia, promoting neuroinflammation via miR-146a sponging, a pathway paralleling its role in MASLD lipid accumulation but differentiated by brain-specific myelin disruption [232,233,236]. Overall, these associations highlight ncRNAs as central hubs in lipid-mediated chronic disease progression, with shared mechanisms (e.g., PPAR modulation) but divergent endpoints, vascular inflammation in CVD, insulin resistance in metabolic/hepatic conditions, and neuronal apoptosis in neurological disorders, underscoring the need for integrated therapeutic strategies.

5. Therapeutic Targeting Strategies, Biomarker Potential and Delivery Technologies of ncRNAs in Lipid-Related Chronic Diseases

NcRNAs play pivotal roles in regulating lipid metabolism, positioning them as promising tools for diagnostics and treatments in chronic conditions like atherosclerosis, MASLD/NASH, and obesity. Their stability in biofluids, often protected by EVs or HDL particles, enables non-invasive detection of disease-specific signatures [326]. The therapeutic potential of ncRNAs stems from their central roles in lipid metabolism, inflammation, and vascular homeostasis. Manipulating their expression can reverse disease phenotypes in preclinical models, providing a foundation for novel interventions. For instance, liver-specific miR-122 knock-out rapidly develops NASH because of enhanced lipogenesis, alterations in lipid secretion, and increased TNF-α secretion [108], or lncRNA-MALAT1 silencing upregulated the expression of SR-A in oxLDL-stimulated macrophages. SR-A-mediated uptake of modified LDL by macrophages leads to deposition of cholesterol and foam cell formation during atherogenesis [211]. ncRNAs’ dynamic changes enable real-time monitoring of progression or therapy response. Despite hurdles like delivery challenges, off-target effects, and ncRNA network complexity, these approaches herald precision medicine for lipid disorders.

5.1. Therapeutic Targeting Strategies

5.1.1. Antisense Oligonucleotides (ASOs) and antagomiRs

ASOs and their miRNA-specific subclass, antagomiRs, represent a powerful therapeutic strategy to precisely inhibit pathogenic ncRNAs driving lipid disorders [327,328]. These synthetic, chemically modified nucleic acid analogs are designed to bind complementary target ncRNA sequences via Watson–Crick base pairing [329]. For instance, miR-33 antagomirs represented a promising gene therapy system for lipid metabolic disorders. MiR-33 antagomirs can significantly decrease lipid deposition in the liver and treat MASLD [330]. In acute bronchial asthma, inhibition of miR-21 with an antagomir reduced allergic airway inflammation by blocking Th2 cell activation, indicating the potential of this antagomir as a therapeutic approach for asthma [331]. A study demonstrated that conditional silencing with a cholesterol-conjugated antagomir (antagomir-126) effectively suppressed miR-126 expression in endothelial cells and lung tissue, confirming the utility of lipid-based delivery for miRNA inhibition. Loss of miR-126 activity was associated with reduced capillary density and impaired endothelial outgrowth, effects attributable to the derepression of angiogenesis inhibitors such as Spred-1 and PIK3R2 [332]. In recent years, several ncRNA-based therapeutics have advanced into human clinical trials, especially siRNA and ASO modalities targeting lipid regulators. One of the most prominent examples is Inclisiran (a GalNAc-conjugated siRNA targeting PCSK9), which in two phase III trials reduced LDL-C by ~52.6% relative to placebo in patients with elevated LDL cholesterol [333]. In long-term follow-up, inclisiran has shown a durable lipid-lowering effect and favorable safety over multiple years [334]. Another example is Vupanorsen, an ASO directed against ANGPTL3 mRNA (GalNAc-conjugated). In phase II studies, it effectively lowered triglycerides and atherogenic lipoproteins in patients with metabolic and lipid disorders [335,336]. However, concerns about hepatic fat accumulation and liver enzyme elevations limited further development [337]. To overcome some of those limitations, newer siRNA agents have entered trials. For instance, Zodasiran, a hepatic siRNA targeting ANGPTL3, in the ARCHES-2 (phase IIb) study led to dose-dependent reductions in triglycerides (up to –63%), LDL, non-HDL, and apoB in patients with mixed hyperlipidemia, without a significant rise in liver fat [338,339]. In parallel, Plozasiran (ARO-APOC3), a hepatocyte-targeted siRNA against APOC3, demonstrated in the SHASTA-2 trial (phase IIb) robust reductions in fasting triglycerides (~–57% at higher doses) in patients with severe hypertriglyceridemia [340,341,342,343]. Another attractive target is Lipoprotein(a) [Lp(a)]. The siRNA Olpasiran has shown potent Lp(a) lowering: in a randomized clinical trial, it significantly reduced Lp(a) levels in patients with established cardiovascular disease [344,345]. Complementing siRNAs, classic ASOs targeting LPA also persist in development. For example, Pelacarsen, an ASO against LPA, has shown substantial Lp(a) reduction in phase II, and is now being tested in the Lp(a)HORIZON trial to evaluate the impact on major cardiovascular events [346,347]. Together, these studies underscore the therapeutic versatility of ASOs, antagomirs and siRNA-based therapy, demonstrating their potential to modulate diverse disease pathways ranging from lipid metabolism to inflammation and angiogenesis.

5.1.2. MiRNA Mimics and Inhibitors

Restorative strategies using miRNA mimics offer a complementary approach to antisense inhibition for ncRNA-based therapeutics. These synthetic, double-stranded RNA molecules are engineered to replace the function of tumor-suppressive, metabolic diseases, or anti-steatotic miRNAs that become downregulated in disease states [348]. For instance, the study investigated the therapeutic potential of using a miR-122 mimic and/or a miR-221 inhibitor as a novel treatment approach for hepatocellular carcinoma in an animal model. When administered together, these molecules enhanced the individual therapeutic effects by specifically regulating SENP1 and ARF4. This dual strategy was shown to suppress tumor cell growth and angiogenesis, while at the same time promoting both apoptosis and necrosis in cancer cells [349]. In vascular endothelial cells, introducing either a miR-223 mimic or a miR-223 inhibitor altered Tissue Factor (TF) expression at both the mRNA and protein levels. These findings demonstrate that miR-223 negatively regulates TF expression, revealing a new molecular mechanism in the control of the coagulation cascade and offering insight into potential protection against thrombogenesis during atherosclerotic plaque rupture [350]. Collectively, these findings highlight the promise of miRNA mimics and inhibitors as therapeutic tools, capable of restoring protective miRNA functions to regulate tumor progression, metabolic imbalance, angiogenesis, and vascular homeostasis.

5.1.3. Multi-Omics and Gene-Editing Approaches

The regulatory interactions between ncRNAs and lipid metabolism are multifaceted and span transcriptional, post-transcriptional, and metabolic levels. To disentangle these connections, multi-omics strategies, notably combining transcriptomics with lipidomics or proteomics, have been increasingly employed to identify ncRNA–lipid correlations. For example, in the context of cholesterol homeostasis, the lncRNA LeXis is induced by LXR signaling and acts as a feedback regulator of cholesterol biosynthesis, thereby linking lipid-sensing pathways with non-coding transcriptome control [351]. On the miRNA side, miR-33 has been well characterized; it suppresses expression of ABCA1 and ABCG1, thus inhibiting cholesterol efflux to HDL and contributing to cellular cholesterol retention [352]. Although direct applications of CRISPR-based editing on ncRNAs in lipid disease models remain scarce, a few key studies illustrate the feasibility of such approaches. For instance, CRISPR/Cas9-mediated knockout of miR-24 in primary mammary epithelial cells led to reductions in cholesterol and monounsaturated fatty acids, along with modulation of lipid biosynthesis genes like FASN and INSIG1 [353]. On the technical front, dual-guide RNA (dgRNA) CRISPR strategies have been developed for efficient and specific deletion of miRNA regions without off-target disruption of homologous miRNAs [354].

5.2. Biomarker Potential

Numerous studies have demonstrated that ncRNAs detectable in biofluids (plasma, serum) serve as promising non-invasive biomarkers in disorders of lipid metabolism. For example, miR-122 is significantly elevated in the plasma of patients with liver disease, correlating with alanine aminotransferase and histologic damage [355,356]. In MASLD cohorts, miR-122-5p, along with miR-21, miR-126-5p, and miR-151a-3p, is higher in individuals with steatosis and correlates with hepatic fat content and liver stiffness [357]. Similarly, miR-34a shows elevated serum levels in patients with MASLD/NASH compared to healthy controls or patients with other liver diseases; its levels correlate with the severity of steatosis and inflammatory activity, and the diagnostic accuracy area under the receiver-operator characteristic curve (AUC) is promising [358,359,360]. On the lncRNA side, circulating lncRNA ENST00000416361 demonstrates notable upregulation in the plasma of patients with coronary artery disease (CAD), approximately 2.3 times higher than in healthy subjects, and exhibits a receiver operating characteristic (ROC) AUC of 0.79, supporting its potential utility as a non-invasive diagnostic biomarker for CAD [361]. Another lncRNA, CoroMarker, present in EVs, shows high stability in plasma and strong diagnostic performance for CAD (AUC ~ 0.92) independent of classical risk factors [362,363]. Low lncRNA LeXis, which regulate cholesterol homeostasis, independently associate with NASH diagnosis in patients with NAFLD. Therefore, circulating lncRNA LeXis could be a potential non-invasive diagnostic biomarker for NASH [24]. lncRNA CHROME, which is elevated in the plasma and atherosclerotic plaques of individuals with CAD, regulates cellular and systemic cholesterol homeostasis [242]. These findings support the utility of ncRNAs both as diagnostic biomarkers (steatosis, NASH, dyslipidemia, CAD) and for monitoring disease progression or response to therapy, complementing existing lipid and liver function markers.

5.3. Delivery Technologies

Overcoming the delivery barrier is paramount for translating ncRNA therapeutics into clinical reality, as naked RNA molecules are rapidly degraded by nucleases, exhibit poor cellular uptake, and lack tissue specificity. Some of the advanced delivery systems described below overcome these limitations by employing sophisticated engineering approaches.

5.3.1. Lipid Nanoparticles (LNPs)

Encapsulation of a miR-122 mimic in LNP-DP1 effectively increased miR-122 levels in tumor cells, suppressed tumor progression in vivo, and demonstrated superior delivery efficiency compared to conventional approaches [364]. In addition, a study explored the use of PEGylated lipid nanoparticles (PEG-LNPs) for delivering anti-adipogenic miRNAs as a potential therapy for obesity and type 2 diabetes. Loading miR-27a suppressed adipogenesis by downregulating PPARγ and reducing lipid droplet formation, while miR-26a promoted browning of white adipocytes through UCP1 upregulation. These findings demonstrate that targeted miRNA delivery via PEG-LNPs may provide a novel strategy to modulate adipose tissue function in metabolic diseases [365]. Nanoliposome-mediated delivery has also been employed as an ideal nano-scale delivery system for cancer diagnosis and therapy. Nanoliposomes are synthetic lipid-based nanoparticles engineered to encapsulate and deliver therapeutic agents, including ncRNAs. Unlike EVs, which are naturally secreted, nanoliposomes provide a controllable and versatile platform for targeted drug delivery [366]. Cationic nanoliposomes were developed as carriers for miR-1296 to overcome delivery barriers in triple-negative breast cancer (TNBC). The nanoliposomes showed high encapsulation efficiency, effective cellular uptake, and cytoplasmic localization of miR-1296, leading to reduced viability of TNBC cells through apoptosis and enhanced sensitization to cisplatin [367].

5.3.2. GalNAc-Conjugates

A type of delivery system used in RNAi therapeutics, particularly for targeting liver cells. They utilize the sugar molecule N-acetylgalactosamine (GalNAc) to bind to the asialoglycoprotein receptor (ASGPR) on liver cells, facilitating efficient cellular uptake of the therapeutic molecule, such as siRNA. This targeted delivery enhances the effectiveness of RNAi, a process that silences specific genes, for treating various liver-related diseases [368]. For instance, a study optimized in vitro models to replicate inclisiran (a representative GalNAc–conjugated siRNA) metabolism in vivo, identifying rat serum/plasma, liver homogenates, liver tritosomes, and plated hepatocytes as effective systems. These models closely mimic liver metabolism and nuclease activity, providing valuable tools for studying GalNAc-conjugated siRNA therapeutics and supporting the optimization of siRNA drug development [369]. GalNAc-conjugated siRNA (ANGsiR10) was developed to silence ANGPTL3, a key regulator of lipid metabolism. The GalNAc modification enables targeted delivery to hepatocytes via the asialoglycoprotein receptor, enhancing potency and durability. In vitro and in vivo studies showed that ANGsiR10 effectively reduced ANGPTL3 expression, resulting in marked and sustained decreases in plasma triglycerides and cholesterol. These findings highlighted the therapeutic potential of GalNAc-siRNA conjugates for long-acting management of dyslipidemia and liver diseases [370].

5.3.3. Engineered EVs

EVs are nanoscale particles that can be categorized into subtypes such as exosomes, ectosomes, microvesicles, and apoptotic bodies. They are secreted by a wide range of cell types, including immune cells, mesenchymal stem cells, endothelial, epithelial, and various cancer cells. EVs naturally carry diverse biomolecules, such as proteins, DNA, mRNA, miRNAs, and lncRNAs. They have been detected in multiple body fluids, including plasma, serum, saliva, cerebrospinal fluid, breast milk, urine, and semen. By being released into these fluids, EVs serve as key mediators of intercellular communication [371]. EVs are being explored as delivery systems for miRNA therapeutics through two main approaches: endogenous loading, where RNA is incorporated during EV formation, and exogenous loading, where RNA is introduced after EV isolation. In one study, HEK293T cells were engineered to load pre-miR-199a into EVs via a TAT–TAR interaction, which increased packaging efficiency by about 65-fold while preserving proper maturation into functional miRNA. Despite this improvement, the overall yield remained very low (~0.003 copies per EV), meaning billions of EVs were needed to observe transfer, and the delivered miRNA levels were too low to affect target gene expression in recipient cells [371]. Exosome-mediated delivery, as an EV-based delivery, was examined by miRNA-155 mimicker or inhibitor and found to have a significant biological response in hepatocytes and macrophages. B cell-derived exosomes can function as vehicles to deliver exogenous miRNA-155 mimic or inhibitor into hepatocytes or macrophages, respectively [372]. Engineered EVs have also been shown to efficiently deliver siRNAs into stem cells and in vivo models with minimal toxicity, supporting their potential for stem cell engineering and RNA-based gene therapies [373]. These findings highlight the potential of EVs as versatile carriers for therapeutic ncRNAs, though their efficiency and consistency in cargo loading remain key challenges to overcome.

5.3.4. Aptamer-Functionalized Systems

Aptamers are single-stranded RNA or DNA molecules that form hairpin and additional secondary structures determined by specific sequences to achieve target recognition. Aptamer-guided delivery systems are emerging as promising strategies for non-coding RNA (ncRNA) therapy. For instance, in castration-resistant prostate cancer, a 19-nt RNA aptamer (EpDT3) that specifically binds to cancer cells that overexpress EpCAM on the cell surface and are endocytosed after binding to the molecule, was conjugated to poly (amidoamine) (PAMAM) dendrimers to facilitate efficient delivery of the tumor suppressor lncRNA-MEG3 (pMEG3). The resulting PAMAM-PEG-EpDT3/pMEG3 nanoparticles enhanced cellular uptake through aptamer-mediated endocytosis and showed superior anti-tumor efficacy compared to non-aptamer-modified nanoparticles. Both in vitro and in vivo experiments confirmed that aptamer functionalization significantly improves ncRNA delivery and therapeutic outcomes [374]. In clear cell renal cell carcinoma (ccRCC), AS1411 aptamer-modified lipid nanoparticles (AS1411/LNP) were used to deliver siRNA targeting circPDHK1. This aptamer-guided system improved tumor-specific uptake, prolonged circulation, and effectively reduced circPDHK1 levels, leading to inhibition of proliferation, migration, and mTOR-AKT signaling in ccRCC cells, with minimal off-target toxicity [375]. These studies collectively demonstrate that aptamer-functionalized delivery platforms offer a versatile and effective approach for targeted ncRNA therapy across diverse cancers.

6. Conclusions

In conclusion, ncRNAs orchestrate multi-layered interaction networks that sustain systemic lipid homeostasis. These networks function inter-organically, mediating crosstalk between the liver, adipose tissue, brain, vasculature and kidney, while intra-organically fine-tuning tissue-specific responses through interactions with inflammatory and oxidative stress pathways. This integration enables ncRNAs to synchronize metabolic flux, inflammation, and redox signaling across organs, thereby preserving physiological equilibrium or, upon dysregulation, propagating diseases such as MASLD, obesity, and cardiovascular disorders through amplified lipotoxicity and impaired lipid trafficking. MiRNAs are key regulators of lipid metabolism, exerting control by simultaneously targeting multiple genes. They bind to mRNAs and repress the expression of enzymes (e.g., HMG-CoA reductase [HMGCR], FASN), lipid transporters (e.g., ABCA1, CD36), and transcription factors (e.g., PPARα, SREBP-1c) that govern lipid synthesis, oxidation, and trafficking. In chronic diseases such as atherosclerosis, T2D, MASLD, and AD, dysregulated miRNA expression disrupts lipid homeostasis, leading to lipid accumulation, inflammation, and progressive pathology. LncRNAs regulate lipid metabolism by interacting with RNA-binding proteins, miRNAs, and chromatin-modifying complexes, thereby modulating key transcriptional regulators such as SREBP-1c, PPARs, and LXR. Through these interactions, they fine-tune the balance between lipid synthesis and catabolism. When dysregulated, lncRNAs disrupt this equilibrium, promoting lipid accumulation, inflammation, and metabolic dysfunction in chronic diseases. CircRNAs regulate lipid metabolism by functioning as miRNA sponges, molecular scaffolds, and transcriptional regulators. Through these roles, they modulate lipid-metabolizing enzymes, transporters, and transcriptional programs, thereby fine-tuning lipid biosynthesis, cholesterol efflux, and adipogenesis. Dysregulation of circRNAs disrupts lipid homeostasis, driving lipid accumulation, inflammation, and the progression of metabolic diseases. Finally, ncRNAs regulate lipid metabolism and are promising biomarkers and therapeutic targets for disorders like atherosclerosis, MASLD, and obesity. They influence lipid balance, inflammation, and vascular health, but translation is limited by delivery and stability challenges. Advances such as antisense oligonucleotides, miRNA mimics, and engineered delivery systems (e.g., lipid nanoparticles, GalNAc conjugates, EVs, aptamers) are helping overcome these hurdles, supporting their potential in precision medicine.