The majority of miRNAs are generated through two primary steps: First, in the nucleus, the primary transcript (pri-miRNA) is processed by RNA polymerase II and the double-stranded RNA-binding protein complex Drosha/DiGeorge syndrome critical region gene 8 (DGCR8) to produce the miRNA precursor (pre-miRNA). Second, in the cytoplasm, the pre-miRNA is further processed by the type III RNA nuclease and the transactivation-responsive RNA-binding protein complex Dicer/TAR RNA-binding protein to generate the mature miRNA form (33). The human miR-155 gene is located within the third exon of the BIC gene on chromosome 21. The mature sequence of miR-155 is highly conserved across evolution, specifically targeting the 3'-UTR of target gene mRNAs through its seed sequence (comprising nucleotides 2-8 at the 5' end), thereby mediating post-transcriptional gene silencing or mRNA degradation (34). Argonaute protein 2 binds to the miR-155 double-stranded complex, forming the core of the RNA-induced silencing complex and producing single-stranded DNA molecules (34). The precursor miRNA hairpin has two arms that can generate biologically active mature miRNAs. The miRNA derived from the 5' arm is referred to as miR-155-5p, while that from the 3' arm is referred to as miR-155-3p. Notably, miR-155-5p exhibits higher biological activity (34) (Fig. 1). Additionally, miR-155 is expressed not only in hematopoietic cells but also in a wide range of tissues, including reproductive tissues, fibroblasts, epithelial tissues and the central nervous system (35-37).

miR-155 is a highly conserved miRNA, and its expression is tightly regulated at multiple levels, including transcriptional regulation, post-transcriptional modifications and epigenetic control (38-40) (Fig. 2). The physiological expression of miR-155 is essential for immune homeostasis, while pathological dysregulation contributes to the progression of various diseases, including AS, stroke and hyperlipidemia (41-43).

The transcription of miR-155 primarily relies on the synergistic action of cis-regulatory sequences and trans-regulatory elements in the promoter region (12,44). Activation of toll like receptors (TLRs) or cytokines (such as TNF-α and IFN-γ) within inflammatory signaling pathways induces miR-155 expression by activating transcription factors such as NF-κB and adaptor protein complex-1 (AP-1), which directly bind to the miR-155 promoter region (38,39). In B and T cells, antigen receptor (B cell receptor/T cell receptor) signaling activates downstream transcription factors (such as STAT3) through the PI3K/AKT or MAPK pathways, promoting miR-155 expression (36,45). Additionally, the transcriptional activity of the BIC gene can be dynamically regulated by DNA methylation and histone acetylation. For example, reduced methylation of the miR-155 promoter region in tumors is closely associated with its upregulation (46).

The maturation of miR-155 involves the cleavage of pri-miR-155 to pre-miR-155 and cytoplasmic transport of pre-miR-155, a process regulated by RNA binding proteins such as KH-type splicing regulatory protein (KSRP). KSRP binds to the stem-loop structure of pri-miR-155 and recruits the Drosha-DGCR8 complex to promote the processing of pri-miR-155 into pre-miR-155 (37). Lineage protein 28 (LIN28) family proteins (LIN28A/B), as RNA-binding proteins, can selectively block the maturation of miRNAs such as let-7 by inhibiting the processing of pri-miRNAs by Drosha/Dicer complexes (47). We hypothesized that LIN28 may regulate miR-155 through a similar mechanism, although further research is needed to confirm this. Additionally, competitive endogenous RNAs (ceRNAs) can indirectly modulate the functional activity of miR-155 by sequestering it via the 'sponge effect'. For example, long non-coding RNAs (lncRNAs) such as feline leukemia virus subgroup C receptor 1-antisense RNA 1 can bind to miR-155, thereby reducing its inhibition of target genes (40). Lu et al (48) identified that circNr1h4 acted as a ceRNA interacting with miR-155-5p, subsequently influencing the pathological progression of renal damage in salt-sensitive hypertensive mouse models.

In disease environments, the expression of miR-155 is often dysregulated due to imbalanced regulatory networks (49). Specifically, the activation of cancer-related genes (such as MYC) or suppression of tumor-suppressor genes (such as TP53) within the tumor microenvironment can trigger persistently elevated levels of miR-155, enhancing cellular proliferation and metastasis (50-52). For instance, overexpression of the BIC gene increases miR-155 levels in diffuse large B-cell lymphoma (53). During chronic inflammatory conditions, sustained inflammatory stimuli [such as high levels of oxidized low-density lipoprotein (ox-LDL) in AS] maintain miR-155 expression, promoting eNOS production and exacerbating tissue damage through continuous activation of the NF-κB signaling pathway (54). Furthermore, in patients with rheumatoid arthritis, synovial fibroblasts aberrantly activate miR-155 via the Janus kinase (JAK)-STAT pathway, leading to the release of inflammatory mediators, including IL-6 and TNF-α (55). Wang et al (56) demonstrated that C1q tumor necrosis factor related protein 12 (CTRP12) could mitigate AS by enhancing reverse cholesterol transport and reducing vasculitis through the miR-155-5p/liver X receptor α (LXRα) pathway. However, it remains unclear whether CTRP12 directly regulates miR-155-5p (56). A study (57) utilizing cerebral I/R injury (IRI) mouse models has demonstrated that upregulated expression levels of lncRNA opioid receptor Mu 1 (Oprm1) alleviated cellular apoptosis induced by cerebral IRI via the Oprm1/miR-155/GATA binding protein 3 (GATA3) pathway. However, the direct regulatory relationship between Oprm1 and miR-155 remains undetermined (57).

AS represents a pathological condition characterized by inflammatory responses and lipid accumulation, serving a role in the progression of CCVDs (69). The pathogenesis of AS involves a prolonged immunological inflammatory process, initiated by various pro-inflammatory mediators interacting with multiple cell types, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and monocytes/macrophages (25,54,70). miR-155, a versatile miRNA, is highly expressed in atherosclerotic plaques of both murine and human subjects (71), emerging as a critical molecular factor in controlling the initiation and progression of AS (Fig. 4).

ECs serve as the interface between the blood vessel wall and the bloodstream, facilitating the exchange of oxygen and nutrients between the blood and tissues (72). ECs serve a pivotal role in inflammation responses, thrombosis regulation and vascular tone modulation, directly influencing CVD progression (72). eNOS generates nitric oxide (NO), a crucial molecule for maintaining cardiovascular homeostasis. Aberrant eNOS expression is often linked to endothelial dysfunction and CVD (73,74). Sun et al (75) demonstrated that miR-155 directly targeted eNOS, where elevated miR-155 levels reduced eNOS expression and NO production in HUVECs, impairing acetylcholine-mediated endothelium-dependent vasodilation in human mammary arteries. miR-155 is co-expressed with the angiotensin II type I receptor (AT1R) in ECs and VSMCs. The molecular mechanism involves miR-155 binding specifically to the 3'-UTR of AT1R mRNA, inhibiting its translation, and thus, mitigating the pathological effects of angiotensin II (Ang II) on HUVECs (76). This finding highlights the pivotal role of the miR-155-AT1R axis in vascular function regulation. EC apoptosis is a form of endothelial injury and is closely associated with the development of AS (73,74). Lee et al (77) demonstrated that G protein subunit α12 protected HUVECs from serum withdrawal-induced apoptosis by maintaining miR-155 expression. Additionally, another study demonstrated that overexpression of miR-155 inhibited palmitic acid-induced apoptosis, reactive oxygen species (ROS) production and inflammatory cytokine release in HUVECs by suppressing the Wnt signaling pathway (78). Endothelial autophagy, as a cytoprotective mechanism, maintains endothelial homeostasis by clearing damaged organelles and misfolded proteins, serving a critical role in preventing the onset and progression of AS (79,80). Under physiological conditions, ECs utilize autophagy to remove ox-LDL and ROS, thereby preventing lipid accumulation and inflammatory cytokine release (81). In HUVECs, ox-LDL induces autophagy and elevates miR-155 expression. Increased miR-155 levels promote autophagy, while reduced miR-155 expression suppresses autophagic activity in vascular ECs (82). Further research by Yin et al (83) indicated that elevated miR-155 levels enhanced ox-LDL-mediated autophagy in HUVECs by inhibiting the PI3K/AKT/mTOR signaling pathway. Metabolic abnormalities and genetic variations in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia and endothelial dysfunction, which are both hallmark features of AS and key contributors to CVD (84). Research by Witucki and Jakubowski (85) demonstrated that metabolites of Hcy elevated the expression levels of miR-21, miR-155, miR-216 and miR-320c, which in turn reduced autophagy in human ECs, a process critical for maintaining vascular homeostasis. The stress-responsive enzyme heme oxygenase-1 (HO-1) protects cells under stress conditions and promotes endothelial anti-inflammatory and vasodilatory responses (86). Pulkkinen et al (87) showed that miR-155 exerted a protective effect on endothelial inflammation by reducing the translation of BTB domain and CNC homolog 1 (BACH1), which induced HO-1 expression in ECs. Another study demonstrated that both Abelmoschus esculentus and metformin ameliorated endothelial inflammation induced by a high-fat diet in rats through enhanced miR-155 expression, primarily by inhibiting TNF receptor associated factor 6 and NF-κB p65 activation (88). Yang et al (89) found that miR-155 not only regulated hypoxia-inducible factor 1α (HIF-1α) expression under hypoxic conditions but also enhanced the angiogenic potential of ECs by targeting E2F transcription factor 2. Promoting angiogenesis is a key feature of healthy ECs.

VSMCs serve a critical role in maintaining vascular function (90). A study revealed that TNF downregulated protein kinase G1 via NF-κB-dependent miR-155-5p biosynthesis, impairing the maintenance of the NO/cGMP-mediated VSMC contractile phenotype and vasodilation (91). The NF-κB/miR-155-5p/protein kinase G axis may contribute to atherosclerotic intimal hyperplasia (91). Another study found that miR-155, induced by NF-κB, disrupted the contractile phenotype of VSMCs and inhibited NO-mediated vasodilation by downregulating soluble guanylate cyclase β1 subunit (sGCβ1) expression, leading to functional impairment of VSMCs (26). Overexpression of miR-155-5p reduces AKT1 levels by inhibiting AKT1 phosphorylation, suppressing VSMC proliferation and migration (92), as well as reducing VSMC apoptosis (71). Furthermore, overexpression of miR-155-5p alleviates oxidative stress and migration of VSMCs by inhibiting BACH1 expression (93). Notably, miR-155 has been reported to downregulate the NADPH oxidase activator 1-phagocyte oxidase protein 47-related signaling pathway in apolipoprotein E (ApoE)^-/- mice, inhibiting VSMC migration and excessive proliferation, thereby attenuating AS progression in these mice (94).

The inflammatory process driven by macrophages serves a critical role in AS (54). ox-LDL induces distinct miR-155 expression within atherosclerotic lesions and macrophages (41,54). Huang et al (41) demonstrated an increase in miR-155 expression under high ox-LDL level conditions, where elevated miR-155 levels suppressed TNF, IL-6 and IL-8 production by inhibiting MYD88-dependent NF-κB pathway activation. Further investigation demonstrated that miR-155 accumulated in ox-LDL-stimulated EC-derived extracellular vesicles (EVs), which were subsequently transferred to human monocyte THP1 cells (41). These vesicles promoted monocyte activation by shifting the monocyte/macrophage balance from the anti-inflammatory M2 phenotype to the pro-inflammatory M1 phenotype (95). These studies highlighted that miR-155 serves a role in negatively regulating the inflammatory response induced by ox-LDL across various signaling pathways (41,95). CTRP12 is a conserved homolog of adiponectin, which may participate in the development of CVDs by promoting endothelial injury or the inflammatory response (23). Wang et al (56) demonstrated that CTRP12 reduced miR-155-5p levels, leading to increased expression of its target gene LXRα. This elevation enhanced ATP binding cassette transporter A1 (ABCA1) and ATP binding cassette transporter G1-mediated cholesterol efflux, promoting macrophage differentiation towards the M2 phenotype, suppressing inflammation and alleviating AS (56). However, one study has suggested that miR-155 may also facilitate AS development (54). Specifically, during AS progression, miR-155 enhances NF-κB pathway activation by downregulating Bcl-6 expression, thereby promoting NLRP3 activation. Bcl-6 expression amplifies the pro-inflammatory transformation of monocytes/macrophages, accelerates lipid accumulation in plaques, and contributes to the formation of an inflammatory microenvironment (54). This illustrates the multifaceted role of miR-155.

The accumulation of foam cells is a key pathological feature of AS (96). One study has shown that miR-155 inhibited foam cell formation in macrophages by promoting cholesteryl ester hydrolase expression (97). Li et al (98) identified elevated miR-155 levels in both plasma and atherosclerotic plaques of patients with AS. In AS animal models, the specific molecular mechanism involved TNF-α inflammatory signaling triggering NF-κB pathway activation, thereby promoting upregulation of miR-155 expression. Elevated miR-155 levels reduced chronic inflammation via a negative feedback mechanism and operated through the miR-155-calcium regulated heat stable protein 1-TNF-α signaling cascade, exerting a protective effect during foam cell formation associated with AS (98).

Vascular inflammation is a key contributor to the development of AS (69). Wu et al (25) demonstrated that miR-155 overexpression suppressed TNF-α-induced endothelial inflammatory responses by reducing the expression of NF-κB p65 and adhesion molecules (such as intercellular adhesion molecule-1 and VCAM-1), thereby decreasing monocyte-EC adhesion. Conversely, miR-155 inhibition enhanced p65 levels and endothelial inflammation, while p65 knockdown using small interfering RNA reversed this effect. Their study further revealed that TNF-α induced miR-155 expression, and this induction was attenuated by endogenous p65 deficiency, suggesting miR-155 may act as a negative feedback regulator to mitigate excessive inflammation triggered by TNF-α (25). Zhu et al (99) found that miR-155 expression was elevated in both AS mouse models and patients with coronary artery disease (CAD) compared with healthy controls. Operating within a negative feedback loop, miR-155 suppresses inflammatory cytokine production, with its expression decreasing as the condition progresses (99). Additionally, miR-155 has been shown to mediate inflammatory responses and the MAPK pathway by targeting MAP3K10 (99). Ye et al (100) revealed that miR-155 served dual roles in AS mouse models: It directly inhibited SOCS1 expression, while increasing phosphorylated-STAT and programmed cell death 4 (PDCD4) levels, as well as increasing the production of inflammatory mediators such as IL-6 and TNF-α. Suppression of miR-155 reduced these molecular levels of PDCD4, STAT, IL-6 and TNF-α. Therefore, it is suggested that miR-155 mediates inflammatory cytokine production in AS through the SOCS1-STAT3-PDCD4 axis (100). Furthermore, miR-155 knockout reduces CD4⁺ T cell-induced EC apoptosis and promotes VSMC proliferation (101). By suppressing miR-155 expression, inflammation related to CD4⁺ T cells is diminished through decreased lymphocyte proliferation and altered differentiation patterns (101). Additionally, miR-155 has been shown to activate NLR family pyrin domain containing 3 (NLRP3) inflammasomes by regulating the MEK/ERK/NF-κB pathway, contributing to atherosclerotic plaque formation in ApoE^-/- mice (102). These findings suggest that miR-155 holds promise as both a biomarker for AS and a potential target for therapeutic interventions.

miR-155 is a critical regulator involved in cardiac inflammation and hypertrophic responses (103-106). Bao and Lin (107) observed a marked increase in miR-155 levels in the myocardial tissue of mice with Coxsackievirus B3-induced myocarditis. Functional experiments in vitro showed that miR-155 mitigated myocardial damage by inhibiting the NF-κB pathway (107). Macrophage infiltration is a hallmark of viral myocarditis, and Zhang et al (108) found that silencing of miR-155 reduced viral myocarditis-induced cardiac damage and dysfunction by promoting macrophage M2 phenotype polarization. Additionally, inhibition of miR-155 improved experimental autoimmune myocarditis in mice by enhancing the Th17/regulatory T cell (Treg) immune response (109). These findings suggest that miR-155 suppression could serve as an effective treatment for autoimmune myocarditis. Zhang et al (110) demonstrated that Astragalus mongholicus (Fisch.) Bge alleviated immune imbalances in peripheral Tregs in children with viral myocarditis by reducing miR-155 levels. Collectively, these studies (107-109) position miR-155 as a promising diagnostic biomarker and potential therapeutic target for cardiomyopathy.

Research has also indicated a decrease in miR-155 levels in animal and patient models of myocardial hypertrophy (111-113). Overexpression of miR-155 induces hypertrophy in H9C2 cardiomyocytes in vitro (114). Conversely, inhibition of miR-155 alleviates myocardial hypertrophy in H9C2 rat cardiomyocytes by downregulating angiotensin II receptor subtype 1 (AGTR1) and inhibiting the calcium signaling pathway activated by AGTR1 (115). Seok et al (116) found that the absence of miR-155 protected the heart from pathological cardiac hypertrophy, primarily by reducing jumonji and AT-rich interaction domain containing 2 expression. Another study revealed that EVs derived from hypertrophic cardiomyocytes activated the miR-155-mediated MAPK (ERK, JNK and p38) pathway, inducing macrophage inflammation and exacerbating myocardial cell damage (117). Studies have demonstrated that miR-155-overexpressing macrophages directly targeted and suppressed FoxO3a expression in cardiomyocytes of uremic mice via EVs, leading to reduced FoxO3a levels, which promoted cardiomyocyte pyroptosis, and exacerbated hypertrophy and fibrosis (118,119). Additionally, Fan et al (120) demonstrated that resveratrol, a polyphenol compound, alleviated cardiac hypertrophy and improved cardiac function by activating BRCA1 in cardiomyocytes. This mechanism involved BRCA1 activation, which suppressed miR-155 expression, thereby enhancing FoxO3a expression and reducing cardiac hypertrophy (120). Furthermore, Yuan et al (121) demonstrated that cytoskeleton regulator RNA (CYTOR) deletion decreased IKKI protein expression, while IKKI deficiency triggered cardiac hypertrophy via the AKT and NF-κB pathways. miR-155 suppression partially attenuated the effects of CYTOR. The authors proposed that CYTOR functions as a ceRNA for miR-155, counteracting miR-155-mediated inhibitor of nuclear factor κB kinase subunit ε suppression, thus offering protection against cardiac hypertrophy (121). These studies highlight the critical role of miR-155 in cardiac hypertrophy (117-121) (Fig. 5).

MI is an acute cardiovascular event resulting from the rapid reduction or interruption of coronary blood flow, leading to ischemia, hypoxia and necrosis of myocardial cells. The primary cause is coronary atherosclerotic plaque rupture or thrombosis (122). Plaque rupture often results from an imbalance between macrophage-mediated degradation and fibroblast repair functions (123). Wang et al (124) found that upregulated miR-155 was predominantly present in macrophages and fibroblasts in the damaged heart, while pri-miR-155 was exclusively expressed in macrophages. Mice deficient in miR-155 exhibited increased proliferation of cardiac fibroblasts and collagen production, along with reduced inflammation in the damaged heart (124). Notably, suppression of miR-155 reduces nerve growth factor expression by decreasing the phagocytic activity of M1 macrophages and the inflammation mediated by the SOCS1/NF-κB pathway, thereby mitigating sympathetic remodeling and ventricular arrhythmias induced by MI in mice (125,126). Pro-inflammatory macrophage-mediated degradation of connexin 43 (Cx43) serves a pivotal role in arrhythmia following MI (127). A study has demonstrated that miR-155 inhibited the downregulation of macrophage-mediated IL-1β and MMP7 expression via the SOCS1/NF-κB pathway, reducing Cx43 degradation after MI (128).

Aging impairs the function of human mesenchymal stem cells (MSCs), reducing their therapeutic potential in MI (129). Hong et al (130) showed that inhibition of miR-155-5p suppressed MSC aging through the Cab39/AMPK signaling pathway. This suggests that miR-155-5p could be a novel target for restoring the vitality of bone marrow MSCs and enhancing their cardioprotective effects (130). Guo et al (21) also found that miR-155 levels dynamically increased in the hearts of mice with MI and in neonatal rat ventricular myocytes injured by hydrogen peroxide (H₂O₂). Downregulation of miR-155 promoted apoptosis induced by MI by targeting RNA binding protein Quaking (21). Hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis serves a critical role in MI pathogenesis. Inhibition of miR-155-5p can prevent NLRP3 inflammasome activation by targeting sirtuin 1 (SIRT1), thus reducing H/R-induced cardiomyocyte pyroptosis (131). lncRNA XIST promotes cardiac fibroblast proliferation and extracellular matrix (ECM) accumulation by acting as a sponge for miR-155-5p, thus facilitating MI formation (132). Another study demonstrated that in a mouse model of MI with dyslipidemia, the deletion of the miR-155 gene did not reduce infarct size or chronic HF but decreased the density of myofibroblasts in ischemic scars (133). An investigation into miR-155-based therapeutic strategies has revealed that rosuvastatin potentially reduces cardiovascular events and inflammatory markers (INF-γ, TNF-α and IL-6) in patients with acute coronary syndrome by suppressing the miR-155/Src homology 2-containing inositol 5-phosphatase 1 (SHIP-1) signaling cascade (134). Furthermore, combination of American ginseng with Danshen increased the serum levels of hepatocyte growth factor and basic fibroblast growth factor in acute MI rats, enhanced myocardial microvascular density and CD31 levels, and suppressed the miR-155-5p/HIF-1α/VEGF pathway, promoting angiogenesis, compared with those in the acute myocardial infarction model group (135). These findings highlight the potential of miR-155 as a target for the treatment of MI (Fig. 5).

IRI refers to the pathological phenomenon where tissue, such as cardiac or brain tissue, experiences restored blood flow after a period of ischemia, but this restoration exacerbates cell damage (136). This process is commonly observed in vascular recanalization therapies (such as thrombolysis and percutaneous coronary intervention surgery), cardiac or cerebrovascular surgeries, and organ transplantation following acute MI or IS (137,138). IRI poses a challenge in the field of CCVDs, highlighting the urgent need for the identification of novel therapeutic targets.

miR-155 expression increases in myocardial tissue following IRI, which is associated with elevated levels of TNF-α, IL-1β, CD105 and caspase-3, as well as enhanced leukocyte infiltration (139). Knockout of miR-155 reduces inflammatory cell recruitment and decreases ROS production in white blood cells (139). Notably, miR-155 exacerbates the inflammatory response, leukocyte infiltration and tissue damage in IRI by regulating SOCS-1-dependent ROS production (139). Chen et al (20) found that inhibition of miR-155 reduced the MI area by specifically regulating HIF-1α, inhibited IRI-induced cardiomyocyte apoptosis, maintained MMP levels and alleviated myocardial injury in rats. Furthermore, inhibition of miR-155 led to targeted regulation of Bcl-2-associated athanogene 5 and MAPK/JNK signaling, reducing myocardial IRI and the size of MI (140). Another study found that, in IRI mice, miR-155 was expressed at high levels, while SIRT1 expression was low. The expression levels of SIRT1, confirmed to be a target gene of miR-155, were increased following sevoflurane treatment, which reduced miR-155 levels, improved cardiac function, reduced infarct size and inhibited myocardial cell apoptosis (141). Greco et al (142) observed that myocardial IRI-induced EVs exhibited pro-inflammatory features, exacerbating cardiac injury. The specific molecular mechanism involved these EVs transferring miR-155-5p to macrophages, thereby enhancing the inflammatory response via activation of the JAK2/STAT1 pathway (142). This suggests that targeting EVs could be a potential therapeutic approach for the management of IRI. An investigation has demonstrated that miR-155 deletion improved cardiac ultrasound measurements in IRI mice, with reductions in MI areas, myocardial fibrosis and cellular apoptosis (including reducing the expression levels of caspase-3, caspase-4 and caspase-11) (143). Investigation of the underlying mechanism revealed that decreased miR-155 expression increased SH2 domain-containing protein tyrosine phosphatase 2 levels and alleviated IRI-induced necroptosis by suppressing ERK1/2 pathway activation (143). These findings highlight the potential of miR-155 as a key therapeutic target in the treatment of myocardial IRI (Fig. 5).

The elimination of the miR-155 gene protects against brain injury and hemorrhagic transformation induced by I/R (142). Multiple studies have corroborated these findings. Jiang et al (144) found that miR-155 deficiency reduced NO production and eNOS expression by activating the Notch pathway, thereby alleviating the damage caused by cerebral I/R in mice with middle cerebral artery occlusion (MCAO). Inhibition of miR-155 increases cell viability and reduces apoptosis by targeting the nuclear factor erythroid 2-related factor 2/HO-1 pathway, preventing neuronal damage induced by cerebral I/R (65). Furthermore, downregulation of miR-155 mitigates IRI by targeting V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog B, improving the neurological function and inhibiting inflammatory responses [IL-1β, IL-6, TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2] (145). Another study also found that in MCAO/reperfusion mouse models and oxygen glucose deprivation/reoxygenation (OGD/R)-induced SH-SY5Y cells, miR-155-5p targeted dual specificity phosphatase 14 (DUSP14) by regulating the NF-κB and MAPK signaling pathways, thereby accelerating cerebral IRI (146). Suppression of miR-155-5p reduces cellular apoptosis and cerebral injury (146). Research by Shi et al (147) revealed that decreased miR-155-5p expression alleviated cerebral I/R-induced inflammation and cell death by modulating the DUSP14/thioredoxin interacting protein/NLRP3 signaling cascade. Notably, increased expression of lncRNA Oprm1 mitigates apoptosis following cerebral I/R damage via the Oprm1/miR-155/GATA3 regulatory axis (57). Furthermore, elevated Parkinson's disease protein 7 expression suppresses miR-155 levels, thereby enhancing SHP-1 expression and modulating astrocyte activation during cerebral IRI (148). These findings suggest potential therapeutic strategies for managing cerebral IRI (Fig. 6).

HF is a clinical syndrome characterized by a decline in the pumping function of the heart, leading to an inability to meet the metabolic needs of the body, with common symptoms including dyspnea, fatigue and fluid retention (149). The etiology of HF encompasses conditions such as hypertension, coronary heart disease and cardiomyopathy (150). The underlying pathological mechanisms involve myocardial remodeling, inflammation and fibrosis (151). Li et al (152) utilized bioinformatics and experimental validation to investigate the potential role of miR-155 in HF. The authors found that miR-155 may regulate the viability and apoptosis of H9c2 cardiomyocytes by targeting and modulating G protein-coupled receptor 18 (152). In the same year, another study reported that in established rat and cell models of HF, overexpression of Sirt1 upregulated NF-κB p65 and miR-155, promoting brain-derived neurotrophic factor (BDNF) expression and reducing cardiomyocyte apoptosis. The authors proposed that Sirt1 alleviated HF in rats via the NF-κB p65/miR-155/BDNF signaling cascade (153). Gao et al (154) found that schisandrin protected rat cardiomyocytes and prevented congestive HF by regulating miR-155 expression and mediating the AKT/cAMP response element-binding protein (CREB) signaling pathway. Another study revealed that miR-155 expression was downregulated in the myocardial tissue of mice with HF. Overexpression of miR-155 inhibited myocardial cell apoptosis (via inhibition of Bax and downstream caspase-3) through HIF-1α, reducing cardiac function damage in HF mice (155). These studies (152-154) highlight the critical role of miR-155 in myocardial protection and suggest its potential for improving cardiac function through the regulation of specific molecules (for example, HIF-1α, AKT and CREB) (Fig. 5).

Elevated miR-155 levels in the circulation of hypertensive patients have been found to be positively associated with inflammatory markers, indicating their involvement in the pathological process of hypertension through immune regulation (68,156). Animal models have confirmed that miR-155 deficiency alleviates perivascular inflammation and reduces blood pressure (157). Yang et al (68) demonstrated that levamlodipine improved vascular inflammation and endothelial dysfunction by regulating miR-155 in hypertensive rats, thereby modulating the receptor activator of nuclear factor κ-B/receptor activator of nuclear factor κ-B ligand/osteoprotegerin pathway. Additionally, studies have shown that miR-155 regulates vascular tone and endothelial-dependent vasodilation by targeting the eNOS and vascular endothelial growth factor signaling pathways (75,158). Overexpression of miR-155 can inhibit eNOS activity, reducing NO production, promoting endothelial dysfunction and contributing to hypertension development (75). VSMCs are essential for maintaining vascular function, and inflammation-induced VSMC dysfunction can also lead to hypertension (159). Park et al (26) found that miR-155, induced by NF-κB, downregulated sGCβ1 expression, impaired the VSMC contractile phenotype and disrupted NO induced vasodilation, leading to VSMC functional damage. Another study revealed that in the tunica media (VSMCs) of hypertensive rats, miR-155 expression was elevated. Inhibition of miR-155 reduced systolic and diastolic blood pressure, increased expression of p27 and α-smooth muscle actin (α-SMA) in the tunica media, and decreased the thickness of the tunica media. These findings suggest that miR-155 has therapeutic potential for hypertension, with its expression levels being positively associated with vascular wall thickness (160).

Ang II is a key peptide hormone in the renin-angiotensin system, serving a critical role in regulating vasoconstriction and renal sodium reabsorption (161). The physiological and pathophysiological effects of Ang II are primarily mediated through AT1R (162). Zheng et al (157) found that overexpression of miR-155 in cells reduced Ang II-induced α-SMA expression, suggesting that miR-155 may regulate the differentiation of rat aortic adventitia fibroblasts and inhibit AT1R expression. Additionally, research has shown that vascular mineralocorticoid receptors promote vasoconstriction and increase blood pressure with age by modulating miR-155 (163). Specifically restoring miR-155 in aged mineralocorticoid receptor-intact mice reduces calcium voltage-gated channel subunit α1 2 and AgtR1 mRNA levels, alleviating L-type calcium channel-mediated and Ang II-induced vasoconstriction and oxidative stress (163). Atrial natriuretic peptide (ANP), secreted by primary atrial myocytes, lowers blood pressure by increasing cGMP levels, inducing vasodilation, diuresis and sodium excretion (164). Vandenwijngaert et al (165) found that compared with individual use of miR-425 or miR-155, the combination of miR-425 and miR-155 demonstrated greater suppression of natriuretic peptide A expression and cGMP production in cardiomyocytes. These studies showed that promoting the expression of miR-155 may represent an effective strategy for regulating blood pressure in hypertensive disorders (163-165).

Stroke is the second leading cause of death worldwide, and IS is a major subtype (166). miR-155 serves a role in the progression of IS (167,168). With ongoing research, the molecular mechanisms of miR-155 in protecting against IS are becoming clearer (Fig. 6). Xing et al (169) used an in vivo rat model of MCAO and an in vitro oxygen-glucose deprivation cell model to simulate IS onset. The authors found that inhibition of miR-155 could protect against IS by promoting the phosphorylation of S6K through the Ras homolog enriched in brain/mTOR pathway (169). Ischemia induces autophagy via miR-155, contributing to nerve damage (170). Yang et al (170) revealed that miR-155-induced autophagy altered inflammatory responses and exacerbated ischemic brain injury by regulating the TLR4/NF-κB pathway in ischemic brain tissue. Another study indicated that miR-155 worsened cellular damage in IS by activating the TLR4/MYD88 signaling pathway (22). The study by Adly Sadik et al (171) demonstrated that miR-155 may promote inflammatory responses post-IS by activating the JAK2/STAT3 axis. A recent study found that miR-155 inhibited the activation of Wnt/β-catenin signaling, restored the Th17/Treg balance and prevented acute IS in mice (172). These findings highlight that miR-155 is involved in multiple signaling pathways and targets in IS. Knockdown of miR-155 expression and the use of specific inhibitors to block miR-155 targets may offer a novel approach for treating IS by interrupting signaling pathway transmission. Research has shown that geniposide and ginsenoside Rg1 protect against focal cerebral ischemia in MCAO model rats by inhibiting miR-155-5p in microglia following ischemic injury (173). Additionally, Opa-interacting protein 5-AS1 inhibits oxidative stress and inflammation by regulating the miR-155-5p/interferon regulatory factor 2 binding protein 2 axis, alleviating OGD/R-induced damage in HMC3 and SH-SY5Y cells, offering a novel targeted therapeutic molecule for IS treatment (174).

Arterial aneurysms are typically asymptomatic in their early stages, but as the aneurysm expands, the risk of rupture increases, which can lead to fatal bleeding (175). Based on anatomical location, aneurysms are classified into abdominal aortic aneurysms (AAAs), thoracic aortic aneurysms and intracranial aneurysms (IAs) (176). miR-155 promotes macrophage infiltration by upregulating pro-inflammatory factors such as TNF-α and IL-6, suggesting that miR-155 may contribute to the inflammatory process during aneurysm development (24,177). Zhang et al (24) found that inhibition of miR-155 prevented AAA formation by regulating macrophage inflammation. The development of AAA was linked to the proliferation and apoptosis of VSMCs. Their study also found that overexpression of miR-155 increased the levels of MMP-2, MMP-9, iNOS and monocyte chemoattractant protein-1 in ApoE^-/- mouse models, stimulating VSMC proliferation and migration. Another study found that miR-155-5p expression was increased in VSMCs damaged by H₂O₂ or NaAsO₂. Overexpression of miR-155-5p inhibited VSMC survival and promoted aneurysm formation by targeting FOS proto-oncogene (FOS) and Zic family member 3 (ZIC3) (178). These findings suggest that miR-155 could be a therapeutic target for AAA treatment. The degradation of the ECM in blood vessels is another key factor in aneurysm formation. miR-155 enhances the activity of MMP-2/9, accelerating the degradation of collagen and elastin (24). Inhibition of miR-155 can alleviate ECM damage and delay AAA progression (24). Yang et al (178) found that reduced miR-155 expression increased the incidence of IA rupture by upregulating MMP-2 expression, particularly in subjects with the SNP rs767649 genotype. This SNP in the miR-155 promoter reduces its transcriptional activity, suggesting a genetic predisposition to increased aneurysm risk (178). Additionally, another study found that miR-155-5p, derived from tumor-associated macrophages, can target IA formation and macrophage infiltration induced by Gremlin1 (179). These findings highlight miR-155-5p as a potential therapeutic target for IAs.