Advances in the biological functions of miR‑205 in various diseases (Review)

miR-205 exhibits distinct, tissue-specific expression patterns across various malignancies, which underlie its context-dependent dual role in tumorigenesis and cancer progression ( 86 ). It can function either as a tumor suppressor, commonly downregulated in cancers such as renal cell carcinoma ( 87 ), prostate cancer ( 88 ), BC, colorectal cancer (CRC) and melanoma ( 89 ), or as an oncogene, promoting tumor development in malignancies including non-small cell lung cancer (NSCLC) ( 90 ), bladder cancer ( 91 ), ovarian cancer ( 92 ), nasopharyngeal carcinoma (NPC), head and neck cancer ( 93 ) and esophageal adenocarcinoma ( 94 ). This functional dichotomy highlights the complex, microenvironment-dependent regulatory networks that govern miR-205 activity ( Table I ) ( 17 , 93 , 95 – 112 ). Evidence suggests that the loss of miR-205 expression may facilitate mammary gland development ( 95 ). Consistent with its tumor-suppressive role, miR-205 is frequently downregulated in BC, with expression levels inversely associated with malignancy grade ( 96 ). Functionally, Kalinkova et al ( 97 ) demonstrated that restoring miR-205 expression in BC cells inhibited invasion and migration by targeting ZEB1. This anti-invasive effect has been further supported by findings that miR-205 upregulation promotes the epithelial marker E-cadherin while suppressing the mesenchymal marker vimentin ( 98 ). The tumor-suppressive role of miR-205 extends beyond BC. For example, in gastric cancer, Ma et al ( 99 ) reported that miR-205 impeded cell proliferation and invasion by downregulating CXCL11 and inhibiting AKT signaling. Similarly, Wang et al ( 100 ) reported that miR-205 can target cyclin B2 to inhibit proliferation and migration in thyroid cancer cells, where Wang et al ( 101 ) demonstrated that suppression of the PTEN/AKT pathway by miR-205 curbed malignant phenotypes in renal cell carcinoma. The function of miR-205 shows notable context dependence, even within the same cancer type. In ovarian cancer, some studies have described a tumor-suppressive role: miR-205 expression has been reported to be downregulated in ovarian cancer cells, with its overexpression inhibiting proliferation and migration by targeting MAPK10 ( 102 ). Conversely, Cai et al ( 103 ) reported an oncogenic function, showing that miR-205 enhanced invasion in ovarian cancer cell lines (OVCAR-5, OVCAR-8 and SKOV-3) and promoted tumorigenesis by downregulating TCF21, which led to upregulation of MMP2 and MMP10 ( 92 , 103 ). This suggests that the role of miR-205 may vary across different molecular subtypes or stages of ovarian cancer. Similarly, in pancreatic ductal adenocarcinoma (PDAC), evidence points to a dual role: Wang et al ( 104 ) identified elevated miR-205 in plasma-derived EVs and PDAC tissues, whereas EV-miR-205 appeared to suppress metastasis by targeting VEGFA and was negatively associated with lymph node metastasis. miR-205 acts as an oncogene in several malignancies, as demonstrated by its upregulated expression in both tumor tissue and patient serum. In cervical cancer, miR-205 overexpression has been shown to promote proliferation, invasion and migration by directly targeting and downregulating chimerin 1 ( 105 – 108 ). Similarly, in NPC, miR-205 enhances tumorigenesis and progression through multiple mechanisms: It drives cell proliferation and invasion by suppressing calmodulin-1 ( 109 ), and facilitates metastasis via exosome-mediated downregulation of desmocollin-2, which activates the EGFR/ERK pathway and upregulates MMP2 and MMP9 ( 110 ). This oncogenic role is also evident in liver cancer, where miR-205 targets DNAJA1 to promote proliferation and metastasis ( 111 ), and in NSCLC, where it fosters tumor progression by downregulating APBB2 ( 112 ). The functional importance of miR-205 in these types of cancer is further emphasized by regulatory interactions with tumor-suppressive lncRNAs such as VENTXP1, which inhibits head and neck squamous cell carcinoma tumorigenesis by repressing miR-205 and consequently upregulating its target ankyrin repeat domain 2 ( 93 ).

Cancer remains one of the most notable public health challenges worldwide. Although the global disease burden persists, overall cancer-related mortality has declined in recent decades, largely due to the widespread implementation of early screening programs, increased emphasis on preventive strategies and the continuous development of innovative therapeutic modalities ( 1 ). Contemporary oncology has adopted a multidisciplinary and collaborative model of comprehensive care, integrating surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy. In clinical settings, combination chemotherapy continues to represent the standard first-line treatment for metastatic pancreatic cancer. Notably, fluorouracil-based combination regimens have demonstrated superior survival outcomes in patients with advanced pancreatic disease when compared with gemcitabine combined with taxane-based therapies ( 2 ). In addition, multidisciplinary team-guided preoperative interventions serve a pivotal role in optimizing perioperative management and improving outcomes for patients with gastrointestinal malignancies ( 3 ). Beyond conventional treatments, Traditional Chinese Medicine has been shown to exhibit diverse biological activities, including immunomodulatory, anti-inflammatory and direct antitumor effects, thereby providing promising options for adjunctive cancer therapy ( 4 , 5 ). In recent years, nanomedicine has emerged as a transformative approach in oncology, exploiting nanoscale size effects and tunable surface characteristics. Through mechanisms such as targeted drug delivery, controlled release and enhanced immunogenicity, nanoparticle-based systems can synergize with immunotherapy to improve therapeutic efficacy in malignancies such as prostate cancer. In addition, these platforms hold potential for overcoming immune evasion and reshaping the tumor microenvironment ( 6 ). Furthermore, advances in smart nanocarriers and stimulus-responsive drug delivery systems are accelerating the transition of cancer therapy toward greater precision and personalization. Nevertheless, conventional therapeutic strategies continue to face substantial limitations, including treatment-related toxicity, radio- and chemoresistance, and pronounced heterogeneity in therapeutic efficacy across tumor types. For example, survival rates for pancreatic cancer and glioblastoma remain markedly lower than those observed in breast and prostate cancer ( 7 ). Consequently, the identification of novel therapeutic strategies capable of reversing drug resistance, enhancing treatment responsiveness and minimizing adverse effects remains a critical priority and a central focus of contemporary oncology research. MicroRNAs (miRNAs/miRs) are endogenous, non-coding RNA molecules 20–24 nucleotides in length that function as critical post-transcriptional regulators of gene expression. Their principal mechanism involves binding to complementary sequences within the 3′-untranslated regions of target mRNAs, thereby inducing transcriptional repression or translational inhibition ( 8 ). Through this mode of regulation, miRNAs govern a wide spectrum of essential biological processes, including cell proliferation, differentiation, apoptosis and metabolic homeostasis. Notably, individual miRNAs are capable of targeting hundreds of genes and a single gene may be simultaneously regulated by multiple miRNAs, collectively forming highly complex and interconnected regulatory networks ( 9 ). This extensive regulatory capacity underscores the indispensable role of miRNAs in maintaining cellular equilibrium. Accordingly, aberrant miRNA expression has emerged as a defining feature of numerous pathological conditions, including malignant tumors ( 10 ), cardiovascular diseases ( 11 ), neurodegenerative disorders ( 12 ) and immune dysregulation ( 13 ). Advances in high-throughput sequencing technologies and bioinformatics analyses have further emphasized the clinical potential of miRNAs as diagnostic biomarkers and therapeutic targets, firmly establishing them as a central focus of epigenetic research ( 14 , 15 ). In oncology, miRNAs are increasingly recognized for their crucial involvement in maintaining cancer stem cell properties and modulating therapeutic responses, particularly in the development of drug resistance ( 16 ). Among these regulatory molecules, miR-205 exhibits highly context-dependent expression patterns and functional roles that vary substantially across different tissues and cancer types. Its ability to act either as an oncogene or as a tumor suppressor, a phenomenon commonly referred to as a ‘dual role’ in cancer biology, has attracted considerable scientific attention ( 17 ). Beyond oncogenesis, miR-205 also participates in a range of non-malignant pathological processes. The present review systematically summarizes advances in the understanding of miR-205, encompassing its biological characteristics, regulatory mechanisms, functional roles and prognostic importance across diverse diseases. Furthermore, it integrates current evidence on key target genes and signaling pathways associated with miR-205, thereby providing a foundation for the development of precise diagnostic tools and targeted therapeutic strategies.

miRNAs are highly stable molecules that can be reliably detected in various physiological fluids, such as serum and plasma, as well as tissue specimens, using multiple robust technical platforms ( 113 ). Due to their notable potential for elucidating disease mechanisms, and advancing diagnostic and therapeutic strategies, miRNAs have become a major focus of biomedical research ( 114 ). Notably, their application as non-invasive biomarkers for cancer diagnosis and prognosis has garnered substantial interest ( 115 ). Evidence supports the substantial diagnostic and prognostic value of miR-205 in several types of cancer. Re et al ( 116 ) conducted a miRNome analysis using next-generation sequencing on 43 patients with intestinal-type sinonasal adenocarcinoma (ITAC) following surgical resection. This previous study revealed downregulation of miR-205 in tumor tissues, with low miR-205 expression serving as an independent predictor of poorer disease-free survival (DFS) and overall survival (OS), highlighting its potential as a prognostic biomarker for ITAC ( 116 ). Complementing these findings, Li et al ( 117 ) performed a meta-analysis evaluating the diagnostic efficacy of miR-205 in lung cancer, primarily squamous cell carcinoma, involving 564 patients and 667 controls. The analysis demonstrated high diagnostic performance, with a sensitivity of 0.88 (95% CI: 0.78–0.94), specificity of 0.78 (95% CI: 0.66–0.86) and an area under the receiver operating characteristic curve (AUC) of 0.90 (95% CI: 0.87–0.92). The diagnostic odds ratio of 25.86 further underscored its strong potential for lung cancer screening and clinical application ( 117 ). The diagnostic utility of miR-205 is also supported by its detectability in circulating exosomes and EVs. Zhao et al ( 118 ), analyzing data from The Cancer Genome Atlas, reported notable downregulation of exo-miR-205 in patients with CRC, including those with early-stage disease. Although sensitivity (53.6%) and specificity (71.9%) for early-stage CRC were moderate, the notable postoperative increase in miR-205 levels suggested its potential as a dynamic marker for disease monitoring ( 118 ). This aligns with growing interest in EV-derived miRNAs as biomarkers for cancer diagnosis and prognosis ( 119 ). Supporting this, a clinical study by Bang et al ( 120 ) involving 220 subjects found that EV-derived miR-205 was elevated in patients with cancer-associated stroke compared with those with cancer alone, indicating its utility in predicting cancer-related coagulopathies. Similarly, Wang et al ( 121 ) demonstrated markedly elevated serum exo-miR-205 levels in patients with NSCLC relative to controls, further reinforcing its diagnostic relevance. Zhao et al ( 122 ) investigated the diagnostic potential of miR-205 in thyroid nodules by analyzing patient serum samples. This previous study revealed that both miR-205 and thyroid stimulating hormone receptor (TSHR) mRNA expression levels were notably elevated in patients with benign or malignant thyroid nodules compared with those in the controls. For diagnosing thyroid nodules (vs. controls), miR-205 alone yielded an AUC of 0.867, outperforming TSHR mRNA (AUC=0.760). Notably, combining both markers improved diagnostic accuracy, achieving an AUC of 0.896 with a sensitivity of 96.43% and specificity of 76.81% at the optimal cut-off. Additionally, miR-205 and TSHR mRNA maintained moderate diagnostic efficacy in distinguishing malignant from benign nodules, with AUC values of 0.738 and 0.729, respectively. These findings collectively underscored the clinical utility of miR-205, especially when combined with TSHR mRNA, as a valuable biomarker panel for thyroid nodule diagnosis and risk stratification ( 122 ). miR-205 serves a pivotal regulatory role in gynecological malignancies and demonstrates prognostic potential across various types of cancer. A comprehensive meta-analysis by Wu et al ( 123 ), encompassing data from 5,835 patients, revealed that the prognostic impact of miR-205 was highly cancer-type-specific. In BC, elevated miR-205 expression was significantly associated with improved OS [hazard ratio (HR)=0.84, 95% confidence interval (CI): 0.72–0.98, P=0.022]. By contrast, in endometrial cancer, upregulated miR-205 predicted poorer disease-specific survival (HR=2.19, 95% CI: 1.45–3.32, P<0.001), highlighting its dual prognostic role and potential as a therapeutic target in both malignancies ( 123 ). Beyond gynecological cancer, miR-205 also exhibits tumor-suppressive properties in other malignancies. Lu et al ( 124 ) reported marked downregulation of miR-205 in hepatocellular carcinoma (HCC), especially in aggressive tumor subtypes. Lower miR-205 expression was associated with unfavorable clinicopathological characteristics, and shorter DFS and OS, supporting its role as a tumor suppressor and promising prognostic biomarker in HCC ( 124 ). Beyond its prognostic importance, miR-205 has emerged as a critical modulator of tumor chemoresistance, demonstrating the ability to reverse drug resistance across multiple cancer types ( 125 ). The mechanisms underlying this effect frequently involve the inhibition of key resistance-related pathways. For example, in doxorubicin-resistant liver cancer cells (HepG2/DOX), miR-205 overexpression has been shown to restore sensitivity by upregulating PTEN, which suppresses the PI3K/AKT/P-glycoprotein (P-gp) axis and reduces P-gp expression, ultimately inhibiting proliferation and inducing apoptosis ( 126 ). Similarly, in BC, miR-205 overcomes tamoxifen resistance by targeting mediator complex subunit 1 (MED1) and HER3, disrupting the HER3-PI3K/AKT-MED1 signaling cascade ( 127 ). This chemosensitizing role extends to other agents as well; for example, miR-205 enhances cisplatin sensitivity in glioma by targeting E2F1 ( 128 ), and in gallbladder cancer stem cells, its upregulation suppresses both the mRNA and protein levels of PRKCE, thereby inhibiting gemcitabine resistance ( 129 ). Despite their therapeutic potential, the clinical translation of miRNA-based therapies such as miR-205 faces notable challenges, particularly in achieving tumor-specific targeting and efficient in vivo delivery. Conventional targeted therapies often encounter issues including drug resistance, adverse side effects and limited efficacy against metastatic disease, underscoring the urgent need for innovative delivery strategies ( 130 ). Advances in nanomedicine and natural delivery systems offer promising solutions. Nanoparticle platforms, including zinc oxide and selenium nanoparticles, exhibit intrinsic antitumor properties while serving as carriers for therapeutic agents ( 131 ). Additionally, certain plant-derived compounds, such as artemisinin and curcumin, can modulate miRNA expression. Razzaq et al ( 132 ) demonstrated that miR-205, which is typically downregulated in BC, can be effectively restored using plant extracts, nanoparticles or hybrid plant-nano materials, highlighting the potential of these hybrid strategies to sensitize cancer cells and inhibit tumor progression. Lin et al ( 133 ) developed a miRNA delivery system utilizing PLGA nanoparticles conjugated with dual cell-penetrating peptides (CPPs, R9 and p28) to target cutaneous squamous cell carcinoma (cSCC). This previous study demonstrated that CPP-conjugated nanoparticles loaded with miR-205 effectively induced tumor regression in a mouse cSCC model and inhibited the migratory ability of cSCC cells. Flow cytometric analysis further revealed that miR-205 upregulation promoted apoptosis in cSCC cells, thereby suppressing tumor growth. These results suggested that such nanoparticle-based miRNA delivery systems represent a promising therapeutic strategy for tumor treatment ( 133 ). Exosomes have emerged as natural delivery vehicles with superior biocompatibility and targeting abilities compared with traditional biomarkers. For instance, Zhang et al ( 134 ) successfully encapsulated miR-205 within mesenchymal stem cell-derived exosomes, markedly enhancing endothelial barrier function and reducing vascular leakage in an alloxan-induced diabetic mouse model of retinopathy, illustrating a novel, efficient therapeutic approach for vascular diseases. Ybarra et al ( 135 ) first administered miR-205 mimics to diabetic mice via vitreous cavity injection, observing a notable reduction in VEGF levels. This decrease may be associated with improved erythropoietic processes in abnormal blood vessels. Based on these findings, it was proposed that intravitreal injection of miR-205 may be used as a potential therapy for treating angiogenesis ( 135 ). Rubini et al ( 136 ) employed an exosome-based delivery system to administer miRNAs, including miR-205, as a therapeutic intervention for feline idiopathic cystitis. Following treatment, a substantial proportion of cats exhibited symptom relief within a relatively short period, with ~70% showing clinical improvement by day 15. Ultrasonographic evaluations conducted before and after treatment revealed marked morphological changes in the bladder, characterized by the resolution of intraluminal material and restoration of mucosal integrity. These findings indicated a successful therapeutic outcome following the intervention ( 136 ). Baicalin has been shown to upregulate miR-205 expression in hepatocytes, which subsequently targets and inhibits importin α5, leading to inactivation of the NF-κB signaling pathway. This cascade reduces the release of pro-inflammatory cytokines, alleviates oxidative stress and suppresses hepatocyte apoptosis, thereby attenuating the progression of alcohol-associated liver disease. These findings have demonstrated that certain herbal components can exert hepatoprotective effects by upregulating miR-205, highlighting the therapeutic potential of miR-205 in clinical applications ( 81 ). Huang et al ( 50 ) demonstrated that methylation levels in the miR-205 promoter region were increased in methionine-fed mice and Hcy-treated pulmonary microvascular endothelial cells (PMVECs), leading to reduced miR-205 expression. RT-qPCR results indicated that miR-205 reduction aggravate pulmonary vascular dysfunction. These findings indicated that hypermethylation of the miR-205 promoter may represent a key pathogenic mechanism in Hcy-induced PMVEC dysfunction. Overexpression of miR-205 could serve as a potential therapeutic target for protecting against Hcy-induced pulmonary microvascular dysfunction ( 50 ). Zhou et al ( 137 ) used miRNA microarray and RT-qPCR experiments to determine that miR-205 expression levels were downregulated in fresh endometriotic tissue. Subsequently, miR-205 was upregulated in endometrial cells, and was shown to target and suppress angiopoietin-2 (Ang2) expression, thereby activating the ERK/AKT pathway in ectopic endometrial cells. Ang2 is a growth factor belonging to the Ang/tyrosine kinase with Ig and EGF homology domains signaling pathway, one of the main pathways involved in angiogenesis. This inhibition reduced the migration and invasion of ectopic endometrial stromal cells while promoting apoptosis. These findings demonstrated that miR-205 serves as a novel diagnostic biomarker and therapeutic target for endometriosis treatment ( 137 ). Huang et al ( 49 ) demonstrated that upregulation of miR-205 expression reduced lipid accumulation and plaque formation in mouse blood vessels, promoted apoptosis and inhibited cell migration in an in vitro atherosclerotic cell model constructed from human aortic vascular smooth muscle cells induced by oxidized low-density lipoprotein. These experimental results indicated that miR-205 may be used to mitigate the progression of atherosclerosis ( 49 ). Wang et al ( 79 ) discovered that miR-205 expression was elevated in serum exosomes enriched from patients with occupational dermatitis caused by TCE, and it exhibited a notable positive association with liver function injury markers. Furthermore, in mouse models, miR-205 was shown to target and promote RORα protein expression, thereby exacerbating TCE-induced liver injury. Consequently, therapeutic downregulation of miR-205 expression could potentially mitigate liver damage in these mouse ( 79 ). Zhang et al ( 67 ) established a nasal mucosa of OVA-sensitized mouse model of AR and demonstrated via RT-qPCR that miR-205 expression was upregulated in mice with AR. Notably, miR-205 knockdown reduced nasal rubbing and sneezing frequency while alleviating pathological changes in the nasal mucosa, indicating that miR-205 may serve as a potential therapeutic target for AR ( 67 ).

miR-205 is a multifunctional regulator involved in a wide range of malignant and non-malignant diseases. It modulates critical signaling pathways that control fundamental cellular processes such as apoptosis, proliferation, migration, angiogenesis and inflammation. The biological effects of miR-205 are highly context-dependent, influenced by its target genes and the specific cellular environment. In non-malignant conditions, miR-205 serves essential roles in tissue repair, immune-inflammatory regulation, and maintaining epithelial and metabolic homeostasis. Its functions can be paradoxical, for example, it alleviates fibrosis in diabetic nephropathy but may exacerbate inflammation in psoriasis. In cancer, miR-205 dysregulation is closely linked to disease progression, highlighting its potential as a diagnostic and prognostic biomarker, especially via liquid biopsy, as well as a therapeutic target. Targeted delivery of miR-205 mimics or inhibitors using advanced nanocarriers, including exosomes and liposomes, offers promising therapeutic strategies. Additionally, combining miR-205 modulation with conventional treatments may improve therapeutic outcomes. Overall, research on miR-205 enriches the understanding of disease mechanisms and identifies novel therapeutic options. Translating these findings into clinical practice will require sustained efforts to bridge rigorous basic research with thorough clinical validation.

Initially identified in mice and pufferfish, miR-205 is now recognized as an evolutionarily conserved miRNA, with homologs present across species ranging from zebrafish to humans ( 18 , 19 ). In humans, miR-205 is encoded on chromosome 1q32.2. As research has progressed, it has become evident that the biological functions of miR-205 in cancer are highly context-dependent. Whether miR-205 exerts oncogenic or tumor-suppressive effects is largely determined by the cellular microenvironment and the specific gene networks under its regulation ( 17 ). Similar to most miRNAs, miR-205 does not induce cellular phenotypic changes, such as alterations in proliferation, migration or invasion, through the modulation of a single target gene. Instead, it concurrently regulates multiple downstream targets, thereby initiating complex and interconnected signaling cascades. For example, in lung cancer models, downregulation of miR-205 results in the upregulation of the transcription factor zinc finger E-box binding homeobox (ZEB)2, which subsequently suppresses erbB3 expression. This multilayered regulatory axis ultimately enhances tumor cell proliferation and invasiveness, thereby accelerating disease progression. Notably, the reduction in erbB3 expression represents an indirect downstream consequence of miR-205 dysregulation in this context ( 20 ). Beyond tumor biology, miR-205 serves an essential role in maintaining epithelial homeostasis, and regulating tissue repair and scar formation ( Fig. 1 ). Loss of miR-205 disrupts PI3K/AKT signaling, leading to impaired proliferation, adhesion and migration of skin progenitor and stem cells. Such dysregulation can result in defective epidermal barrier formation, abnormal hair follicle morphogenesis, and, in severe cases, neonatal lethality ( 21 ). Supporting these observations, Jiang et al ( 22 ) employed Agilent miRNA microarrays combined with quantitative (q)PCR validation to demonstrate marked downregulation of miR-205 in hypertrophic scar tissue. Functional analyses revealed that miR-205 overexpression suppressed fibroblast migration, scar hyperplasia and collagen synthesis by directly targeting thrombospondin-1. Consistently, Qi et al ( 23 ) reported that miR-205 can inhibit extracellular matrix production through direct targeting of Smad2, thereby attenuating hypertrophic scar formation. Emerging evidence has further indicated that miR-205 participates in regulatory crosstalk involving long non-coding RNAs (lncRNAs) and mRNAs via competition for shared miRNA response elements. In this competitive endogenous RNA (ceRNA) network, lncRNAs can function as molecular sponges for miRNAs, binding to their complementary sequences and relieving repression of miRNA target genes, thus adding an additional layer of post-transcriptional regulation ( 24 ). In the context of keloid formation, Su et al ( 25 ) demonstrated that the lncRNA HOXA11-AS may act as a ceRNA for miR-205. Silencing HOXA11-AS or restoring miR-205 expression significantly inhibited fibroblast proliferation and extracellular matrix deposition while promoting apoptosis, thereby suppressing pro-fibrotic processes. Notably, the functional consequences of miR-205 regulation are highly context-specific. In skin wound healing, Wang et al ( 26 ) reported that miR-205 downregulation facilitated keratinocyte migration and accelerated wound closure by suppressing integrin α5 expression. By contrast, Lin et al ( 27 ) observed a pro-healing role for miR-205 in the cornea, where its overexpression promoted epithelial repair by targeting the potassium channel KCNJ10 and enhancing cellular proliferation. In a normal mammary epithelial cell culture model, miR-205 was found to be highly expressed in progenitor-like cells, where it promoted mammary epithelial differentiation and development through repression of ZEB2 ( 28 ). Beyond epithelial tissues, miR-205 has also been implicated in reproductive biology. Yu et al ( 29 ) reported a marked upregulation of miR-205 in endometrial epithelial cells following ovulation, whereas reduced miR-205 expression was observed in the endometrial tissues of women with infertility. Notably, intrauterine administration of a miR-205 inhibitor during the mid-secretory phase, corresponding to the window of implantation, significantly decreased embryo implantation rates and was associated with altered regulation of ZEB1. These findings suggest a critical role for miR-205 in modulating endometrial receptivity and embryo implantation ( 29 ). Beyond pathological conditions, miR-205 also serves as an important regulator of fundamental physiological processes, including systemic metabolism and cellular differentiation. Its role in metabolic regulation has been highlighted by two independent studies. In hepatocytes, miR-205 suppresses the SHIP2/FOXO signaling axis, thereby reducing hepatic glucose production ( 30 ). In parallel, emerging evidence has suggested that miR-205 enhances intestinal motility by modulating gut microbiota composition and tryptophan metabolism ( 31 ). In the context of cell differentiation, Hu et al ( 32 ) demonstrated that miR-205 overexpression significantly inhibited the osteogenic differentiation potential of bone marrow-derived mesenchymal stem cells (BMSCs). Mechanistically, this effect was mediated through direct targeting of the SATB2/Runx2 signaling pathway, as reflected by the downregulation of key osteogenic markers, including bone sialoprotein, osteopontin, alkaline phosphatase (ALP) and osteocalcin.

The transcriptional regulation of miR-205 is orchestrated by multiple transcription factors, among which p53 serves a central role ( 33 ). Specifically, p53 directly activates miR-205 transcription by binding to a canonical p53 response element (p53RE) located within the upstream promoter region of the miR-205 gene. Through this regulatory axis, miR-205 contributes to the control of critical cellular processes, including cell cycle arrest, apoptosis and the maintenance of genomic stability. Consequently, loss-of-function mutations in TP53 can disrupt this transcriptional activation, representing a key mechanism underlying miR-205 downregulation in several malignancies, such as triple-negative breast cancer (BC) ( 34 ). In addition to p53, the closely related family members p63 and p73 also recognize and bind to p53REs owing to their structural homology with p53, thereby positively regulating miR-205 expression ( 35 ). However, in specific tumor microenvironmental contexts, mutant p53 has been shown to indirectly repress miR-205 transcription by destabilizing p63 and impairing its transcriptional activity ( 36 ). Other transcription factors further contribute to the fine-tuned regulation of miR-205. The transcription factor Sp1 can bind to regulatory regions upstream of the miR-205 host gene under conditions of DNA damage, thereby promoting the co-transcription of miR-205 and its host gene. By contrast, the epithelial-mesenchymal transition (EMT)-associated transcription factor Twist1 directly interacts with the miR-205 promoter to suppress its transcription, linking miR-205 regulation to EMT and tumor progression pathways ( 37 ). DNA methylation is a fundamental epigenetic modification characterized by the addition of a methyl group to the fifth carbon of cytosine residues, resulting in the formation of 5-methylcytosine. Genomic regions enriched in cytosine-guanine dinucleotides, known as CpG islands, are typically located within upstream regulatory elements, particularly gene promoter regions. Aberrant hypermethylation of promoter-associated CpG islands in tumor suppressor genes can lead to transcriptional silencing and functional inactivation, representing a common and critical mechanism driving cancer initiation and progression ( 38 ). Epigenetic modifications, including DNA and histone methylation, serve pivotal roles in a wide range of pathophysiological processes, such as oncogenesis and aging, by regulating gene expression, modulating chromatin architecture, influencing protein function and affecting RNA processing. Among these mechanisms, DNA methylation is essential for maintaining genomic stability, organizing higher-order chromatin structure and precisely controlling transcriptional activity ( 39 ). Accumulating evidence has indicated that the expression of specific miRNAs, including miR-205, is frequently regulated by aberrant DNA methylation during disease development, particularly in cancer, where CpG island hypermethylation commonly leads to the silencing of tumor-associated miRNAs ( 40 ). For miR-205, CpG sites are densely distributed within both the promoter region of its host gene (MIR205HG) and the miRNA coding locus itself ( 34 ). In HER2-positive BC, activation of the HER2/Ras/Raf/MEK/ERK signaling cascade induces the upregulation of DNA methyltransferases, resulting in hypermethylation of the MIR205HG promoter and consequent transcriptional repression of miR-205 ( 41 ). This epigenetic silencing contributes to BC progression, as reduced miR-205 expression is associated with the enhanced proliferation, invasion and migratory capacity of cancer cells. Thus, elucidating the methylation-dependent regulation of miR-205 not only expands the understanding of miRNA-mediated oncogenic signaling in BC but also highlights potential avenues for epigenetically targeted therapeutic intervention. Supporting this regulatory paradigm, Mancini et al ( 42 ) reported coordinated histone modifications at the miR-205 locus in prostate cancer cells, including increased levels of the repressive mark H3K27me3 and reduced enrichment of the activating mark H3K4me3. Together, these chromatin alterations may synergize with DNA methylation to enforce stable silencing of miR-205 ( 42 ). Similarly, epigenetic mechanisms have been implicated in EMT during lung cancer progression. Tellez et al ( 43 ) demonstrated that EMT initiation was preceded by chromatin remodeling characterized by H3K27me3 accumulation, which was subsequently consolidated by DNA methylation, leading to permanent repression of miR-200b, miR-200c and miR-205. Downregulation of these miRNAs has been shown to be strongly associated with a dedifferentiated phenotype in both immortalized human bronchial epithelial cells and primary lung tumors. Beyond oncology, aberrant methylation of the miR-205 promoter has also been observed in non-malignant disorders. In a cellular model of Parkinson's disease (PD), Wang et al ( 44 ) identified hypermethylation of the miR-205 promoter region. Notably, pharmacological demethylation restored miR-205 expression and suppressed leucine-rich repeat kinase 2 (LRRK2), implicating miR-205 methylation as a critical regulatory mechanism in PD pathogenesis and a potential therapeutic target ( 44 ). Moreover, emerging evidence has suggested that epigenetic regulation of miR-205 may influence immune-related disease outcomes. In the context of COVID-19, Vaz et al ( 45 ) reported that elevated circulating miR-205 levels at hospital admission were associated with an increased risk of adverse clinical outcomes, proposing peripheral blood miR-205 as a potential prognostic biomarker for predicting progression to severe or critical disease. Collectively, these findings underscore the central role of epigenetic dysregulation of miR-205 across a broad spectrum of pathological conditions, and highlight its considerable promise as both a prognostic indicator and a target for epigenetically informed therapeutic strategies.