Exploring the role of microRNA-155 as a biomarker and regulatory modulator of target genes in metabolic syndrome

Abstract

Central obesity is one of the defining features of metabolic syndrome (MetS). MetS comprises a cluster of metabolic disturbances including insulin resistance (IR), hypertension, and altered glucose, lipid, and fatty acid metabolism. These alterations are characterized by reduced levels of high-density lipoprotein (HDL) commonly referred to as “good cholesterol” and increased levels of low-density lipoprotein (LDL) or “bad cholesterol”. While HDL protects against cardiovascular disease (CVD), elevated LDL increases disease risk. Collectively, these metabolic abnormalities raise the risk of developing type-2 diabetes (T2D), metabolic dysfunction-associated steatohepatitis (MASH), and CVDs.

The raising global incidence of MetS is largely attributed to sedentary lifestyles, westernization, and the consumption of energy-dense processed foods, making it a growing public health concern across the globe. In recent years microRNAs (miRNAs), which are small non-coding RNA molecules (18 to 25 nucleotides), have emerged as important regulators of post-transcriptional gene expression in metabolic and inflammatory pathways. Among these, miR-155 have received considerable attention for its role in immune activation, inflammatory signalling, cancer, and energy balance. MiR-155 modulates key genes involved in insulin signalling, glucose metabolism, and metabolic homeostasis, thereby contributing to overall metabolic control.

Given these roles, circulating miR-155 has arisen as a promising non-invasive biomarker for metabolic abnormalities and a potential therapeutic target in MetS. This review highlights the multifaceted roles of miR-155 and summarizes accumulating evidence supporting its central involvement in the physiological and pathological mechanisms underlying MetS, with implications for early diagnosis and therapeutic development.

Keywords

miR-155 metabolic syndrome inflammation NF-κB obesity

Introduction

Metabolic syndrome (MetS) commonly refers to a cluster of interrelated metabolic abnormalities that commonly occur together, significantly increasing the likelihood of developing type-2 diabetes mellitus (T2DM), obesity, obesity-associated metabolic dysfunction-associated steatohepatitis (MASH), endothelial cell dysfunction-related cardiovascular disease (CVD), and stroke; all of these conditions are inclined by multiple pathological factors.^1–3

The primary characteristics of MetS include central obesity, IR, hypertension, and dyslipidaemia, which is typically defined by elevated triglyceride (TG) levels along with reduced high-density lipoprotein (HDL) cholesterol, commonly referred to as “good” cholesterol.^4–6

Over the past few decades, changes in dietary habits and lifestyle patterns such as increased consumption of high calorie foods, frequent intake of high sugar or high fructose corn syrup, containing beverages, and reduced or lack of physical activity, along with a more westernized, sedentary lifestyle have substantially contributed to the global rise in overweight and obesity.^4,7–9

These lifestyle changes are widely recognized as key contributors to the increasing incidence of MetS, which poses a serious and major public health challenge and concern worldwide.^10–12

Epidemiological studies estimated that approximately 20% to 25% of the world adult population is affected by MetS, with prevalence varying according to age, sex, ethnicity, and geographical region.¹³

Despite extensive ongoing research, the complete molecular and biochemical mechanisms underlying obesity and other clinical hallmarks of MetS remain incompletely understood. However, several studies indicate the growing involvement of environmental, genetic, and epigenetic factors, including small non-coding miRNAs.¹⁴

These non-coding, single-stranded miRNAs, around 18 to 25 nucleotides in length, by controlling gene expression at the post-transcriptional level by interacting with complementary regions of target (mRNAs) are strongly implicated in the pathogenesis of metabolic and inflammatory disorders across eukaryotic cells.^15,16

It is well established that many miRNAs are involved in regulating a wide range of normal and pathological processes including adipocyte differentiation, adipose-tissue expansion, metabolism, appetite regulation, oxidative stress (OxS), and obesity.¹⁶ In recent years, considerable attention has been directed towards understanding miRNAs that are highly involved in the development of metabolic and inflammatory disorders.¹⁷

Current results suggest that the functions and behaviour of miR-155 in MetS are not uniform but vary depending on the metabolic environment.¹⁸ Some studies describe a beneficial role of miR-155, showing that it helps to maintain insulin sensitivity and obesity-related inflammation by regulating key metabolic and immune-associated target genes.¹⁹

Unlike many other miRNAs that influence only a few signaling pathways, miR-155 targets multiple key genes which act as pivotal regulators of macrophage polarization, adipocyte differentiation, and insulin signalling (Table 1). This unique multi-pathway regulatory capacity provides a strong rationale for focusing this review exclusively on miR-155.¹⁸

Table 1.

Multiple target genes of miRNA-155.

Pathway	Target Gene	Function	Effect of miR-155	Reference
Insulin Signalling	SOCS1.	Inhibits JAK/STAT and insulin receptor.	↑-Insulin sensitivity.	20
Lipid metabolism	PPARγ, C/EBPβ.	Adipogenesis and lipid storage.	↓-Lipid accumulation.	21 22
Inflammation	SHIP1, BCL6, TAB2, MAP3K10.	NF-κB and macrophage polarization.	↑-Pro-inflammatory cytokines.	23,24
Insulin Resistance	SOCS1, SOCS3.	Insulin receptor desensitization.	Modulates insulin response.	25
Inflammation	SOCS1-STAT3-PDCD4.	Plaque formation and rupture.	↑ p-STAT and PDCD4, making pro-inflammatory mediators.	26

In contrast, several reports indicate that persistent elevation of miR-155 can disturb metabolic balance and promote the secretion of pro-inflammatory cytokines, predominantly in macrophage already exposed to metabolic stress.²⁷

Because miR-155 shows consistent alterations in obesity, IR, and persistent low-grade inflammation, circulating miR-155 levels are being explored as potential biomarkers to identify individuals at increased risk of MetS and related complications.¹⁹

These findings clearly indicate that the function of miR-155 is highly context-dependent, and understanding this variation is essential for accurately interpreting its role in metabolic diseases.

For this review, relevant literature was collected from PubMed, Scopus, and Google Scholar using keywords microRNA-155, RISC, inflammatory cytokines, NF-κB, JAK/STAT signalling, and miRNA biogenesis. Studies published between 2010 and 2025 were examined, with emphasis on experimental studies, clinical investigations, and mechanistic analyses. Only articles that directly contributed to understanding the molecular, diagnostic, or therapeutic relevance of miR-155 within metabolic disorders were included.

In this review, we focus on examining current and new evidence on how miR-155 influences MetS, outlining the signalling pathways it regulates, and assessing its potential as both a diagnostic RNA biomarker and a therapeutic target. In addition, this review seeks to compare and interpret findings from earlier and recent studies to provide a balanced perspective on the biological and clinical significance of miR-155.

Role of miRNAs in metabolic regulation

MicroRNA biogenesis

miRNAs are short, non-coding RNAs approximately 18 to 22 nucleotide in length that regulate gene expression at the post-transcriptional level by promoting mRNA degradation or inhibiting translation. These molecules are initially transcribed by RNA polymerase II as primary miRNA transcriptions, which are subsequently processed by the Drosha–DGCR8 complex into precursor miRNAs (pre-miRNAs).^28–30 Pre-miRNAs are then exported from the nucleus to the cytoplasm via Exportin-5, where the RNase III endoribonuclease Dicer further cleaves them to generate mature miRNA duplexes. One strand of the duplex is incorporated into RNA-induced silencing complex (RISC), a multiprotein complex containing Ago2 and SND1 ribonucleases, while the passenger strand is degraded.^31–34 The miRNA-loaded RISC binds to complementary sequences within target mRNAs, resulting in translational repression or mRNA degradation. Dysregulation of miRNA biogenesis has been associated with several metabolic and inflammatory disorders, including obesity, IR, and MetS^35–37 (Figure 1).

Figure 1.

MicroRNA biogenesis and post-transcriptional regulation through RNA-induced silencing complex.

Biological functions of miRNAs

miRNAs regulate a broad spectrum of biological processes, encompassing cell proliferation, differentiation, growth, development, ageing and longevity, apoptosis, metabolism, and immune responses. They function as fine-tuners of gene regulatory networks, helping to maintain cellular and metabolic homeostasis by ensuring appropriate expression of target genes under physiological conditions. Through coordinated regulation, miRNAs influence key metabolic processes such as glucose utilization, lipid storage, mitochondrial function, and balance of OxS. By precisely controlling gene expression, miRNAs support essential metabolic functions, including glucose metabolism, lipid handling, mitochondrial activity, and OxS regulation. When miRNA expression becomes dysregulated, these tightly controlled processes are disrupted, contributing to the development of metabolic disorders notably T2DM, CVD, obesity, and non-alcoholic fatty liver disease (NAFLD).^38–41

Functional significance of miRNAs in metabolic regulation

miRNAs are short, non-coding RNA molecules that are not translated into functional proteins but play a crucial role in maintaining metabolic balance. They primarily exert their effects by promoting mRNA degradation or suppressing translation, allowing them to subtly modulate numerous cellular and metabolic pathways.^42,43

Each miRNA is synthesized as a duplex containing two strands (5p and 3p), and aberrant expression, either upregulation or downregulation, enables miRNAs to target a broad spectrum of metabolic genes. Through this mechanism, miRNAs exert pleiotropic effects on insulin signalling, lipid metabolism, inflammation, and vascular integrity.^44–46

In MetS, several miRNAs are dysregulated and contribute to disease initiation and progression by altering critical metabolic and inflammatory pathways. For instance, miR-33a/d regulates cholesterol efflux and fatty acid metabolism by targeting ABCA1 and CPT1A, miR-27a inhibits adipocyte differentiation, miR-122 controls hepatic lipid metabolism, miR-146a modulates inflammatory signalling via TRAF6 and IRAK1, and miR-21 influences insulin signalling and endothelial function.^47–50 Collectively, These miRNAs act as integrators of metabolic and immune pathways, linking nutrient sensing with inflammatory signalling and thereby contributing to IR, dyslipidemia and vascular inflammation observed in MetS.⁵¹

miR-155 biogenesis

miR-155 is encoded within the MIR155HG (miR-155 host gene, also known as BIC) gene located on chromosome 21.⁵² MIR155HG is a multifunctional gene that generates multiple products, including the long non-coding RNA MIR155HG, the mature miR-155 through post-transcriptional processing, and a small peptide reported in specific contexts.⁵³ Transcription of MIR155HG is induced by stimuli peptide reported in specific contexts. Transcription of MIR155HG is induced by stimuli such as high glucose, LDL, and transcription factors, such as master regulators like NF-κB, AP-1, and STAT3.⁵⁴ The primary transcript contains the miR-155 hairpin, which is processed in the nucleus by the Drosha–DGCR8 complex to form pre-miR-155. This precursor is exported to the cytoplasm via Exportin-5 and cleaved by Dicer into a miRNA duplex.^55–57 The resulting miR-155-5p (guide strand) is incorporated into the RISC containing AGO2 or SND1 and associated cofactors such as FMR1 and AEG-1, enabling post-transcriptional modulation of specific target mRNAs.^58–60 The passenger strand is typically degraded (Figure 2).

Figure 2.

miR-155 biogenesis and its effect on different regulatory mechanisms.

Physiological role of miR-155 (which is located on chromosome 21) in immune metabolic homeostasis

Immune cell development and activation

MiR-155 serves a central part in immune homeostasis and immune activity by regulating the development, maturation, and activation of memory B-cells, helper T-cells, macrophages, and dendritic cells, all of which are essential for a coordinated immune response.^61,62

Regulation of atherosclerosis through immune modulation

Its influence on immune cell activity also contributes to the regulation of atherosclerosis, where reduced immune cell infiltration can attenuate vascular inflammation and slow disease progression.^63,64

Influence on metabolic conditions relevant to MetS

miR-155 has been recognized as a vital supervisor of metabolic alterations such as overweight, pre-diabetic states, and hepatic steatosis, which constitute key components of MetS.^65,66

Protective function against metabolic disease progression

Evidence from experimental studies indicates that miR-155, through its coordinated immune-metabolic regulatory effects, may act as a protective factor against the progression of MetS and MASH, a serious liver disease characterized by excess hepatic fat accumulation leading to inflammation and fibrosis.^67,68

Functional impact of aberrant miR-155 in MetS

Aberrant expression of miR-155 exerts significant functional consequences in the development and progression of MetS. Consistent downregulation of miR-155 in obese subjects with MetS, hyperglycaemia, and IR⁶⁹ disrupts multiple regulatory pathways essential for glucose homeostasis. Mechanistically, reduced miR-155 contributes to impaired insulin signalling through the loss of repression of established target genes such as CEBPB, SOCS1, and HDAC4, which act as negative regulators of insulin sensitivity.^70,71 These findings are supported by studies demonstrating that miR-155 levels in peripheral blood negatively correlate with CEBPB expression and HOMO-IR, indicating a functional link between miR-155 deficiency and poorer glycaemic control.⁷²

Previous studies have demonstrated that miR-155 regulates adipogenesis by modulating early transcription factors, including CEBPB and CREB1,⁷³ suggesting that aberrant expression promotes adipocyte dysfunction and lipid imbalance. Consistent with this, miR-155 downregulation has been associated with obesity-related disorders, including IR.⁷⁴ Reduced miR-155 expression has further been observed across multiple metabolic disease contexts, including T2D^73,75–78 and non-alcoholic fatty liver disease,⁷⁹ reinforcing its central role in metabolic dysregulation.

Beyond metabolic pathways, aberrant miR-155 expression also alters inflammatory responses. Reduced miR-155 levels in PBMCs of diabetic patients correlates with elevated inflammatory markers such as TNF-α, IL-6, and NF-κB activity. Supporting this, prior evidence demonstrates that miR-155 directly regulates IL-6, IL-10, and TNF-α production via CEBPB targeting.⁸⁰ Together, these findings indicate that miR-155 dysregulation promotes chronic low-grade inflammation, a defining hallmark of MetS. Conversely, compensatory upregulation of miR-155 in pancreatic β-cells during hyperlipidaemia has been shown to enhance glucose metabolism by suppressing MafB, stimulating GLP-1 production, and improving β-cell adaptation to IR.⁸¹ Loss of this adaptive response in miR-155 knockout mice results in exacerbated obesity, dyslipidaemia, and atherosclerosis.⁸¹

MiR-155 in molecular pathways

Glucose metabolism

High-glucose exposure consistently induces miR-155-5p expression across multiple experimental systems, including cultured cells and animal models.^82–84 Similar upregulation has been observed in glomerular mesangial cells under hyperglycaemic conditions^82,84 and in cardiomyoblasts exposed to elevated glucose levels.⁸⁵ Once elevated, miR-155-5p directly suppresses SOCS1 and SOCS6 by binding to their 3’-UTRs⁸⁶ thereby releasing inhibitory constraints on the JAK-STAT signalling pathway and enhancing its activation.^87,88 Concurrently, miR-155-5p downregulates SIRT1, a key regulator of metabolic homeostasis and autophagy, leading to impaired autophagic activity and a reduced cellular capacity to manage glucose-induced metabolic stress.^89–91 In addition miR-155-mediated inhibition of PTEN further activates the PI3K/AKT/mTOR pathway, reinforcing autophagy suppression and contributing to dysregulated insulin-related metabolic signalling under hyperglycaemic conditions.⁸²

In high-glucose-treated mesangial cells, IncRNA CTBP1-AS2 acts as a molecular sponge for this miR-155, thereby indirectly restoring FOXO1 expression and linking miR-155 to gluconeogenic regulation and oxidative-stress responses.⁸⁴ Moreover, glucose-induced miR-155 expression is attenuated in TLR4-deficient mesangial cells, indicating that inflammatory signalling plays a key role in driving miR-155 expression during metabolic stress.⁸⁴ Collectively, these findings demonstrate that miR-155 integrates hyperglycaemia, inflammation, and intracellular stress response by targeting multiple metabolic regulators, ultimately influencing insulin signalling, autophagy, and glucose homeostasis.

Lipid metabolism

Lipid metabolism contributes critically to the progression of NAFLD, and miR-155 regulates several key transcriptional factors controlling lipid homeostasis, including PPARα, PPARγ,⁹² LXRα,⁹³ SREBP-1c,⁹⁴ C/EBPα,⁹⁵ C/EBPβ,⁹⁵ and SIRT1.⁹⁶ PPARα and PPARγ perform distinct but complementary metabolic functions, with PPARα promoting fatty acid oxidation and PPARγ driving adipogenesis and lipid storage while also influencing lipolysis.⁹⁷ The ability of miR-155 to regulate both PPARγ and PPARα⁹² underscores its central role in balancing lipid oxidation, accumulation, and degradation. Additionally, fatty acid synthesis genes such as FAS, ACC2, and FABP4 are influenced by miR-155-dependent pathways, highlighting its broader involvement in fatty acid homeostasis. LXRα, another major metabolic transcription factor governing cholesterol and fatty acid metabolism, is a validated direct target of miRNA155 in NAFLD.⁹³ The transcription factor C/EBPα, which modulates hepatic glucose and lipid metabolism, is also regulated by miR-155, as demonstrated by its control of C/EBPα expression in adipocytes.⁹⁸ Notably, C/EBPα overexpression has been associated with increased susceptibility to hepatic steatosis.^99,100 Collectively, these findings support the role of miR-155 as a key regulator, acting directly or indirectly on multiple genes involved in lipid metabolism,⁹³ with its metabolic effects arising from the coordinated modulation of several transcriptional factors rather than a single target, influencing lipogenesis and fatty acid handling at multiple molecular levels.

Protein metabolism

MiR-155 regulates protein metabolism through its influence on the PI3K–AKT–mTOR axis, a central pathway governing cellular growth, translation, and metabolic reprogramming. The PI3K–AKT pathway has stood identified as a biomarker for prognosis in diffuse large B-cell lymphoma,¹⁰¹ underscoring its role in controlling metabolic and protein-synthetic processes in tumour cells. Upon activation, AKT stimulates mTOR signalling,¹⁰² a master pathway responsible for initiating protein synthesis through downstream effectors such as S6 kinases and translational regulators. AKT also enhances glucose metabolism, thereby supporting MCL-1 protein synthesis and linking miR-155-mediated pathway activation directly to increased protein production and metabolic flexibility.¹⁰³

Furthermore, AKT promotes cell survival by inhibiting apoptosis through the induction of XIAP expression,¹⁰⁴ reinforcing the role of miR-155 in sustaining protein-dependent survival pathways. MiR-155 promotes PI3K–AKT activation largely by repressing the regulatory subunit p85α, which normally stabilizes p110 while inhibiting its activity under unstimulated conditions.^105,106 By suppressing p85α, miR-155 removes this inhibitory control and concurrently alters PTEN function, collectively amplifying AKT phosphorylation and strengthening mTOR-dependent protein metabolic pathways. These interactions demonstrate that miR-155 enhances protein synthesis, metabolic activity, and cell survival through coordinated activation of AKT–mTOR signalling.¹⁰⁶

Carbohydrate metabolism

Hypoxia triggers a metabolic shift in human B-cells from mitochondrial oxidative phosphorylation towards glycolysis and lactate production, reflecting a reprogramming of carbohydrate metabolism to sustain ATP generation under low-oxygen conditions.¹⁰⁷ Within this metabolic adaptation, miR-155 acts as an important regulator by modulating key hypoxia-associated pathways and molecular components that governs glucose utilization. Specifically, miR-155 regulates the expression of EGLN1, PIK3CA, and VHL genes that directly control the stability and activity of HIF-1α, the master transcription factor coordinating glycolytic gene expression under hypoxic stress.¹⁰⁸

Beyond hypoxia signalling, miR-155 is recognized as a multifunctional oncomiRNA capable of shaping metabolic programs by preventing apoptosis, altering gene expression, and affecting early glycolytic steps, including the glucose phosphorylation.¹⁰⁹ Studies in other malignancies show that loss of miR-155 can abolish glucose uptake, underscoring its essential role in controlling carbohydrate metabolic entry points.¹¹⁰ Mechanistically, hexokinase 2 (HK2) is a straight mark of miR-155 and serves as a key glycolytic enzyme responsible for glucose phosphorylation and commitment to the glycolytic pathway.¹¹¹

Dysregulation of HK2 significantly affects glycolytic flux, glucose consumption, and lactate production, consistent with broader metabolic observations linking enhanced glycolysis to increased lactate output under hypoxic conditions.¹¹² Collectively, these findings illustrate that miR-155 governs carbohydrate metabolism by regulating hypoxia-responsive pathways, glucose utilization, and glycolytic enzyme function, thereby supporting metabolic flexibility during stress and disease.¹¹³

Beyond these molecular pathways, alterations in miR-155 expression have been extensively reported across metabolic and cardiometabolic diseases in clinical settings as summarized in Tables 2 –5.

Table 2.

Insights from past clinical studies on how miR-155 is altered in diabetes.

Serial no.	Conditions	Number	Tissues	Main Findings	Reference
1.	T2D patients were evaluated in comparison with healthy age-matched controls.	60	Serum	A decrease in miR-155 expression was observed in individuals with T2D relative to healthy control.	114
2.	Healthy controls were compared with T1D patients, regardless of whether they had albuminuria.	34	Urinary Extracellular Vesicles	Reduced miRNA-155 was observed in T1D patients with albuminuria versus those without albuminuria and versus healthy controls.	115 –117
3.	The analysis contrasted the diabetic nephropathy group with a cohort of healthy participants.	38	Serum	miR-155 was measured in the diabetic nephropathy group and contrasted with levels in healthy control subjects.	118
4.	T2D patients were evaluated alongside healthy people matched for age.	40	Peripheral blood immune cell fraction	A decrease in miR-155 was seen in people diagnosed with T2D relative to healthy controls.	119
5.	T1D subjects were evaluated alongside healthy control of similar age.	59	Plasma	Elevated miR-155 levels in T1D patients relative to healthy controls.	120
6.	The study compared healthy controls to people with T2D who had no retinopathy, early eye changes, or severe proliferation retinopathy.	80	Serum peripheral white blood cells	T2D patients showed reduced miR-155 versus healthy controls, with further decreases seen in non-proliferative and then proliferative retinopathy.	121
7.	Healthy controls were compared with T2D patients, whether or not they had diabetic neuropathy.	64	PBMCs	Patients with T2D and neuropathy showed decreased miR-155 expression compared to healthy control subjects and diabetic subjects without neuropathy.	122
8.	Patients with type-2 diabetes, stratified based on their albuminuria levels, were compared with age-matched healthy controls.	83	Serum	Lower miR-155 levels observed in T2D subjects, regardless of their albumin excretion status, when compared with healthy control subjects.	123
9.	The study compared two-subsets of T2D individuals those with diabetic nephropathy and those without it.	145	Serum	In individuals with diabetic nephropathy, miR-155 levels were evaluated against those in T2D patients lacking nephropathy revealing a significant association with microalbuminuria.	124
10.	Healthy subjects compared to T2D subjects, including those with diabetic retinopathy and lacking diabetic retinopathy.	170	Plasma	The study contrasted miR-155 expression in T2D subjects who had diabetic retinopathy with that of healthy control subjects and T2D population without the complications.	125
11.	The cohort consisted of chronic hepatitis C patients with and without T2D, a separate group of patients with only T2D, and a healthy control group.	80	Serum	T2D patients exhibited lower miR-155 levels than healthy participants.	126

PBMC = Peripheral blood mononuclear cells; T2D = type-2 diabetes.

Table 3.

Expression profile and function implications of miR-155 in obese individuals.

Study Groups	Number	Biological Source	Key Findings	Reference
Cross-sectional human adipose-tissue study: ATM & adipocytes from normal weight versus obese individuals were compared.	NW: 10 Obese: 6	Macrophages from adipose tissue, adipocytes, plasma.	↑miR-155 in adipose-tissue macrophages in obesity suggests macrophage-derived miR-155 influences neighbouring adipocytes (metabolism, inflammation via targeting PPARγ/GLUT4).	127
Cross-sectional obese adults stratified by MetS versus obese without MetS.	Screening n = 12 (6MetS, 6non-MetS)	Peripheral blood (Circulating miRNAs).	↓ miR-155 in obese individuals MetS versus obese without MetS were compared.	128
Cross-sectional + in vitro + animal: adipose tissue from obese versus normal weight, TNF-α stimulated adipocytes; p65/NF-κB mouse models were compared.	Human adipose-tissue biopsies; obese versus normal weight (N not large) were compared.	Adipose-tissue biopsies (from humans) & in vitro adipocytes were compared.	↑miR-155 expression in adipose tissue of obese versus normal weight, correlated with BMI and TNF-α were compared.	129

ATM = adipose-tissue macrophages; MetS = metabolic syndrome.

Table 4.

miR-155 alterations in NAFLD: key findings from previous studies.

Study Group	Sample size	Sample Type	Findings	Reference
Animal model – mice on a high-cholesterol, high sugar diet for 27 weeks; human NASH liver tissue validation was compared.	Mice: WT versus miR-155 KO; Human: Small human NASH liver samples	Liver tissues	↑miR-155 in the liver with NASH; miR-155 knockout mice showed less steatosis, inflammation, and fibrosis contribute to disease progression.	130
Cross-sectional human study – biopsy-proven NAFLD versus healthy controls were compared.	50 NAFLD, 50 controls (blood); 11 + 11 (liver biopsies)	Peripheral blood, liver tissues	↓miR-155 in NAFLD; overexpression of miR-155 reduced hepatic lipogenesis via LXRα suppression – potential diagnostic biomarker.	131
Mouse genetic study (miR-155 mice) + mechanistic work.	n = 13 Mice (KO versus WT) and cell lines (HepG2/Hep1-6)	Liver tissues, hepatocyte cell lines	↓miR-155 loss altered lipid metabolism, complex phenotype.	132

Table 5.

miR-155 alterations in CVD: key findings from previous studies.

Groups Compared	Number	Tissue(s)	Main Findings	Reference
Cross-sectional patients with angiographically confirmed CAD versus control (Genes cohort)	CAD 69, Controls 30	Plasma	↓ miRNA-155 in CAD compared to healthy controls were compared.	133
Correlation between the levels of miRNA-155 and CSF.	66 CSF 66 Healthy Control	Plasma	↑ miR-155 in patients with CSF compared to healthy controls were compared.	134
Acute viral myocarditis-human + mouse profiling/validation were compared.	Human (small) and Animal models	Cardiac tissue/Plasma	↑miR-155 is upregulated in myocarditis. MiR-155 acts as an adverse mediator in acute myocarditis: drives inflammation and cardiac dysfunction.	135
Human atherosclerotic plaques + translational. mouse models	Human plaque + mice	Plaque tissue	↑miR-155 promotes atherosclerosis by repressing Bcl6 in macrophages; deficiency reduces plaque burden translational relevance to human disease.	136

CSF = coronary slow flow.

Interpretation: Overall, the studies summarized in this table indicate that miR-155 expression is frequently altered in diabetes and its complications, although the direction of change varies depending on disease type, tissue source, and clinical context. While most T2D focused studies report reduced circulating or immune cell miR-155 levels, T1D studies suggest a more complex and sometimes opposing pattern, likely reflecting differences in immune activation. Importantly, many human studies remain cross-sectional, limiting casual interpretation. These findings highlight the need for tissue-specific and longitudinal analyses to better define the diagnostic and mechanistic relevance of miR-155 in diabetic complications (Table 2).

Interpretation: Together, these studies indicate that miR-155 regulation in obesity is highly context-dependent, with clear differences between local adipose-tissue expression and circulating miRNA levels. While adipose-tissue macrophages consistently show increased miR-155 expression linked to inflammatory pathways, circulating miR-155 appears reduced in metabolically unhealthy obesity. This discrepancy suggests that miR-155 may primarily exert local effects within adipose tissue, while systemic levels may be influenced by disease stage or metabolic status. Larger, well-characterized cohorts integrating tissue and circulating miRNA analyses are required to clarify the clinical relevance of miR-155 in obesity and MetS (Table 3).

Interpretation: Studies examining hepatic miR-155 in NAFLD and NASH report contrasting expression patterns, likely reflecting differences in disease stage, model system, and cellular context. While animal studies largely support a pro-fibrotic and pro-inflammatory role for miR-155 in advanced liver diseases, human cross-sectional data suggest reduced circulating and hepatic miR-155 in earlier NAFLD. These findings indicate that miR-155 may have dynamic, stage-dependent functions during disease progression, underscoring the importance of longitudinal human studies integrating tissue-specific analysis (Table 4)

Interpretation: Cardiovascular studies reveal context-dependent regulation of miR-155, with circulating levels often differing from tissue-specific expression. While plasma miR-155 may be reduced in stable coronary artery disease, its elevation in coronary slow flow and acute myocarditis suggests a link with active inflammatory states. In contrast, tissue-level analyses consistently demonstrate a pro-atherogenic and pro-inflammatory role for miR-155 within vascular and cardiac immune cells. These findings emphasize the importance of distinguishing between systemic and local miR-155 regulation when evaluating its clinical and mechanistic relevance (Table 5). Furthermore, the relationship between miR-155 expression levels and clinical outcomes across MetS-associated conditions is summarized in Table 6.

Table 6.

Summary of the relative miR-155 expression and clinical outcomes in different MetS-associated conditions.

Condition	Sample	Expression Association	Survival outcomes	Reference
NAFLD	Peripheral whole blood (control = 50, con = 50) and liver biopsy (n = 11 and control 11)	7.7-fold decrease (0.13-fold expression)	↓miR-155 association with increased expression of LXRα-driven lipogenic genes. ↓ miR-155 is a potential biomarker for NAFLD and shows functional data.	137
Obesity	PBMCs	~2.2-fold decrease (0.46-fold expression)	↓ PBMC miR-155 in obese children, miR-155 was negatively associated with fasting insulin, HOMA-IR, and hs-CRP.	138
Obesity (Adults)	Serum (non-diabetic obese versus lean)	Decreased (fold change not reported)	↓serum miR-155 association with obesity and metabolic traits (negative correlation with BMI, cholesterol with insulin, HOMA-IR, waist).	139
T2D	PBMCs (n = 20 Control and n = 20 T2D)	Decreased (fold change not reported)	↓ miR = 155 in PBMCs of T2D subjects’ correlations observed. Downregulation is not directly driving increased cytokine production in their assay.	140
Cardiometabolic risk in obese patients	PBMCs	Decreased	↓ miR-155 in obese patients.	128

T2D = Type-2 Diabetes.

Interpretation: Across metabolic and cardiometabolic conditions, reduced miR-155 expression is consistently associated with adverse metabolic traits, including IR, dyslipidaemia, and obesity-related inflammation. While several studies support its potential as a circulating or immune cell-based biomarker, variability in sample type, reporting of fold changes, and study design limits direct comparison, importantly functional data suggest that miR-155 may reflect underlying metabolic status rather than directly driving disease progression in all contexts.^128,137-140 Larger, longitudinal studies are needed to define its predictive and prognostic utility (Table 6).

Target genes of miR-155 in metabolic regulation

MiR-155 is a central regulatory microRNA that coordinates multiple metabolic pathways contributing to the onset of obesity, IR, and dyslipidemia, which are core features of MetS. One of its key metabolic targets is SOCS1, which is repressed by miR-155, leading to altered insulin signalling and modulation of glucose uptake in adipose tissue and skeletal muscle. Because SOCS1 also functions as an important regulator of inflammatory signalling, its inhibition by miR-155 influences inflammatory responses and in specific contexts, may impact metabolic outcomes. SOCS1 serves as an important constituent of the JAK/STAT pathway, a key mediator of cytokine activity. Dysregulation of this pathway has been implicated in hyperglycaemic induced tissue injury, including leukocyte infiltration, fibrosis, and aberrant cellular proliferation. Consequently, therapeutic strategies aimed at limiting excessive JAK/STAT activation in diabetes and metabolic disorders are currently under investigation.^141–147

Another major target of miR-155 is PTEN, a negative regulator of PI3K/AKT/mTOR pathway, that plays a critical role in insulin action. By downregulating PTEN, miR-155 modulates PI3K/AKT signalling, thereby influencing insulin sensitivity and insulin secretion from pancreatic β-cells. This regulatory interaction contributes to β-cell functional adaptation but may also predispose to β-cell stress under chronic metabolic conditions, as observed in MetS.¹⁴⁸ MiR-155 also targets MafB a transcription factor essential for maintaining β-cell identity and endocrine function. Suppression of MafB by miR-155 impairs adaptive β-cell responses and contributes to IR, thereby increasing susceptibility to β-cell dysfunction-linked conditions such as diabetes and MetS.^149,150

In lipid metabolism, miR-155 regulates PPARγ, a master transcription factor governing adipogenesis and lipid storage. Inhibition of PPARγ by miR-155 disrupts adipocyte differentiation and lipid accumulation, contributing to obesity and insulin resistance, which are major components of MetS.¹⁴⁸ In hepatic tissue, miR-155 further influences lipid synthesis by targeting of SREBP1, thereby modulating hepatic lipid homeostasis and limiting lipotoxicity, a key driver of NAFLD.¹⁵¹

Beyond its metabolic functions, miR-155 acts as critical immune regulator by modulating inflammatory signalling pathways, particularly the NF-κB signalling axis, a central driver of chronic inflammation. Through its effects on NF-κB-dependent gene expression, miR-155 contributes to the regulation of inflammatory responses in metabolically active tissues such as liver and adipose tissue. This immune metabolic interaction is particularly relevant, as persistent low-grade inflammation is defining hallmark of MetS.^152,153 Several conserved target genes have been experimentally validated to mediate the metabolic and inflammatory effects of miR-155, as summarized in Table 7.

Table 7.

Mechanistic insights into conserved miR-155 target interactions.

Target Gene	Functional role	Effect of miR-155 binding	Reference
SOCS1	Negative regulator of JAK-STAT	↓ SOCS1, ↑-inflammation, ↑-insulin resistance	154
SHIP1(INPP5D)	PI3K/AKT pathway inhibitor	↓ SHIP, ↑AKT signalling, ↑ inflammatory activation	155
C/EBPβ	Macrophage activation and inflammation	↓ C/EBPβ, -TNF-α, IL-6	156
FOXO3a	Oxidative-stress response	↓ FOXO3a- ↑ROS, ↑ lipid accumulation	157
PPARγ	Adipogenesis, insulin sensitivity	↓ PPARγ – impaired lipid uptake and insulin response	158
IKBKE	NF-κB pathway activation	↓ IKK ε- ↑NF- κB activation- ↑ inflammation	159
TAB2	TLR signalling adaptor	↓ TAB2 – ↑ TNF-α/IL-6 production	160
BACH1	Antioxidant	↓ BACH1 – ↑ HO-1 – oxidative stress	161
SMAD2	TGF-β signalling mediator	↓ SMAD2 – altered inflammatory signalling	162
SOCS6	Insulin signalling regulator	↓ SOCS6 – ↑ insulin sensitivity	163
PDCD4	IL-10 modulation, translation regulation	↓ PDCD4 – IL-10 and anti-inflammatory response	164
HIF1α	Hypoxia-induced metabolic shift	↓ HIF1α altered glycolysis and inflammatory response	165

Interpretation: Collectively, the conserved targets of miR-155 span key inflammatory, metabolic, and stress response pathways, underscoring its role as a central regulatory hub rather than a pathway-specific effector. By targeting negative regulators of cytokine and insulin signalling, miR-155 may amplify inflammatory responses while simultaneously disrupting metabolic homeostasis. However, the functional outcome of miR-155 activity appears highly context-dependent, varying with cell type, disease stage, and local microenvironment. This complexity likely explains the divergent expression patterns observed across metabolic and inflammatory disorders (Table 7).

These target-specific mechanisms translate into measurable metabolic effects across multiple experimental models, as outlined below in Table 8.

Table 8.

Functional consequences of miR-155 modulation in MetS-associated models.

Model and disease content	Type of miR-155 manipulation	Key mechanistic findings	Metabolic outcome	Reference
Hypothalamus + HFD	AAV8-Cre Knockdown of miR-155-5p in miR-155	Reduced TLR4-NF-κB microglial activation, decreased pro-inflammatory gene expression	Improved glucose tolerance; reduced early HFD-induced inflammation	166
Liver/Diet induced MASH model	miR-155 KO	In HF-HC-HS dietary model, miR-155 deficiency reduced activation of NLRP3 inflammasome and fibrosis signalling	Attenuated hepatic steatosis, inflammation, and fibrosis in NASH model	167
Obesity	miR-155 KO	miR-155 deletion increases inflammation in WAT expression of brown fat thermogenesis genes	KO mice show resistance to HFD-induced weight gain, lower fat accumulation, and enhanced insulin sensitivity	168
Pancreatic β-cells	miR-155 inhibition	Islet-resident macrophage-derived miR-155 suppresses β-cell PDX1 expression. Inhibition reduces macrophage to β-cell transfer	Improved glucose-stimulated insulin secretion, better insulin sensitivity in liver and adipose in HFD model	169
Trophoblast cells (High glucose)	miR-155 mimic (overexpression)	Direct repression of CEBPB (luciferase validated)	Improved glucose uptake, enhanced insulin responsiveness	170

HFD = high-fat diet; KO = knockout.

Interpretation: Functional studies manipulating miR-155 across central, hepatic, adipose, pancreatic, and placental models demonstrate that the metabolic consequences of miR-155 modulation are highly tissue- and context-dependent. While miR-155 deficiency consistency attenuates inflammatory and fibrotic signalling in liver and hypothalamic models, whole body deletion reveals compensatory inflammatory responses within adipose tissue. In contrast, targeted inhibition of immune cell-derived miR-155 improves β-cell function, emphasizing the importance of intercellular communication in metabolic regulation. These findings collectively indicate that therapeutic targeting of miR-155 may require tissue-specific approaches rather than systemic modulation (Table 8).

Limitations of the study

Although this review integrates a wide array of data on miR-155 in MetS, several caveats remain. To begin with, many mechanistic insights derive from animal or in vitro models, which may not fully mirror human metabolic physiology.¹⁷¹ In addition, clinical studies show inconsistent directions of miR-155 dysregulation; some studies report circulating miR-155 was reported to be downregulated in MetS patients and associated with increased IR,¹⁷² whereas adipose-tissue studies show increased expression in obesity.¹⁷³ Moreover, several investigations rely on small sample sizes or heterogeneous populations, such as peripheral blood miRNome studies, which limits statistical strength.¹⁷⁴ MiR-155 expression is context-dependent, influenced by inflammation, nutrient state, and tissue type, making universal interpretation challenging.¹⁷⁵ Adding to these challenges, variability in assay methodology and normalization strategies reduces cross-study comparability. A final limitation is that long-term human interventional trials testing miR-155 modulation are lacking, leaving its clinical translation uncertain.

Future directions

To enhance the future research to include large, longitudinal human cohort studies to understand whether shifts in miR-155 expression actually drive the development of metabolic disturbances or simply reflect ongoing metabolic stress. At the same time there is a clear need for mechanistic studies using human tissues such as adipose biopsies. Adipose tissue samples and immune cells to verify the major miR-155 targets, including SOCS1, PTEN, CEBPβ, and SREBP1, which have been validated mainly in animal models.¹⁷⁶ Developing standardized and reproducible protocols for miRNA extraction, quantification, and normalization will also be essential as these steps are currently a major source of variability across studies. In addition, integrating multi-omics approaches combining miRNA data profiling with transcriptomic, proteomic, and metabolomic data may help clarify the broader regulatory network controlled by miR-155 in metabolic tissues. On the therapeutic side, more work is needed to optimize tissue-specific delivery systems, such as nanoparticle-based approaches or antagomiR platforms and to test them thoroughly in preclinical models; indeed, systemic delivery of anti-miR-155 via polymer nanoparticles has shown efficacy in mouse models of disease.¹⁷⁷

This is especially important given that long-term human studies evaluating miR-155-targeted therapies are still unavailable. Overall, miR-155 stands out as an important molecular regulator positioned at the interface of inflammation, insulin signalling, adipose biology, and lipid metabolism, making it a promising candidate for both biomarker development and therapeutic intervention in MetS. miR-155 also influences key metabolic genes like SOCS1, PTEN, CEBPB, and PPARγ.

miR-155 directly targets PPARγ in adipocytes.^82,178,179 However, the inconsistency observed across human studies, the tissue-specific nature of its expression, and variation in methodological approaches all indicate that more rigorous and standardized research is needed, strengthening evidence through well-designed human cohorts, careful mechanistic validation and improved therapeutic strategies will be essential for moving miR-155 from an experimental molecule to a reliable clinical tool for metabolic disorder management.

Conclusion

miR-155 acts as a key regulatory molecule in MetS by modulating inflammation, immune responses, and metabolic pathways through its control of multiple target genes. Dysregulation of target genes involved in insulin signalling, lipid metabolism, and immune activation highlights its biological signalling, lipid metabolism, and immune activation across tissues. However, variability in human data underscores the need for well-designed translational studies to establish its clinical relevance.

Footnotes

Acknowledgements

I acknowledge the support of JSS AHER institutions for providing access to academic resources and literature necessary for the preparation of this review article.

List of Abbreviations

T2DM: Type-2 Diabetes Mellitus

SOCS1: Suppressor of Cytokine Signalling 1

PTEN: Phosphatase and Tension Homolog

MafB: V-maf Musculoaponeurotic Fibrosarcoma Oncogene B

PPARγ: Peroxisome Proliferator-Activated Receptor Gamma

SREBP1: Sterol Regulating Element Binding Transcription Factor 1

NF-κB: Nuclear Factor Kappa B

miR-155: microRNA-155

RISC: RNA Inducing Silencing Complex

BIC gene: B-cell integration cluster gene

SMAD4: Suppressor of Mothers against Decapentaplegic homolog 4

ISRE: Interferon Stimulated Response Element

IRF: Interferon Regulator Factor

AP: Activator Protein 1

Foxp3: Forkhead box protein P3

HIF-1α: Hypoxia-Inducible Factor 1-Alpha

NAFLD: Non-alcoholic Fatty Liver Disease

JAK: Janus Kinases

STAT: Signal Transducers and Activators of Transcription

PI3K: Phosphatidylinositol 3-kinase

AKT: Protein kinase B

C/EBPβ: CCAAT/enhancer-binding protein beta

HDAC4: Histone Deacetylase 4

ORCID iD

Prasanna Kumar Santhekadur

Author contributions

PMP: Conceptualization, Writing – Initial draft, Review, and Editing; SOC, SS: Writing: Review and Editing; PKS: Conceptualization, Supervision, Writing – Review and Editing, Supervision. All the authors reviewed and approved the final version of the article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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