NAFLD, a metabolic disorder of escalating global incidence, is intricately linked to hepatic insulin resistance and aberrant lipogenesis (38). LXRα orchestrates hepatic lipid homeostasis through transcriptional regulation. Recent studies utilizing palmitic acid (PA)-treated cellular models have uncovered that hyperlipidemic stress induces widespread remodeling of protein arginine asymmetric dimethylation, concurrent with PRMT3 upregulation, lipogenic protein induction, and triglyceride accumulation (7). Functional analyses in HEK293 cells revealed that PRMT3 overexpression promotes lipogenesis via the LXRα signaling axis, manifested by augmented fatty acid biosynthesis and lipid droplet formation. Molecularly, PRMT3 acts as a transcriptional coactivator by binding to LXRα, thereby enhancing its chromatin occupancy and target gene expression. Notably, hepatic tissues from NAFLD patients exhibit elevated PRMT3 expression and increased LXRα-PRMT3 interaction.

Chronic lipid overload drives the progression from fatty liver to hepatocellular carcinoma (HCC) through induction of inflammatory responses, oxidative stress, and metabolic reprogramming, culminating in fibrosis, cirrhosis, and oncogenesis (39). Epidemiological data demonstrate that NAFLD patients face a dose-dependent increased risk of HCC development compared to non-NAFLD counterparts (40). Hyperlipidemic microenvironments activate macrophage inflammatory programs such as the NF-κB signaling pathway, indicating that PRMT3 may potentiate inflammatory responses through lipotoxicity-mediated mechanisms (41). However, while PRMT3 inhibitor SGC707 reduces serum lipids, it fails to alleviate atherosclerosis (42), indicating tissue-specific effects. Mechanistically, SGC707 decreases hepatic triglyceride content and VLDL secretion but paradoxically elevates hepatic cholesterol and plasma bile acids, concurrently inducing pruritus through undefined pathways (43), implicating neuroimmune regulatory roles (Figure 2).

The glycolysis-inflammation axisacts as a central hub linking cellular metabolism and immune responses (44). Aberrant activation of the glycolysis-inflammation axis drives the progression of a wide range of diseases, forming a pro-cancer network through metabolic products, signaling pathways, and immunosuppressive cells, myeloid-derived suppressor cells (45). This process promotes tumor growth, metastasis, and treatment resistance. Metabolic enzymes such as glyceraldehyde 3-phosphate dehydrogenase and LDHA act as in vivo substrates of PRMT3, thus further regulating glycolysis. Moreover, studies have shown that PRMT3 is a critical regulator controlling the switch from oxidative phosphorylation to glycolysis in cancer cells, and cancer cells with high PRMT3 expression rely on glycolysis for their metabolic processes. (46).

In HCC, Lei et al. (36) established PRMT3 overexpression as an independent prognostic indicator. High PRMT3 levels correlate with advanced tumor stage and aggressive phenotypes, while genetic ablation of PRMT3 suppresses HCC cell proliferation and glycolytic flux. Mechanistically, PRMT3 methylates LDHA at arginine 112 through its catalytic E338 residue, augmenting LDHA enzymatic activity. This post-translational modification potentiates glycolysis, sustaining oncogenesis and lactate-mediated acidosis. The resulting tumor microenvironment promotes M2 macrophage polarization, underscoring PRMT3’s role in metabolic reprogramming and immune evasion. Despite its clinical utility, oxaliplatin resistance remains a major therapeutic obstacle. Shi et al. (17) identified PRMT3 as a determinant of chemoresistance, with high PRMT3 expression predicting poor outcomes. Proteomic analysis revealed IGF2BP1 as a novel PRMT3 substrate, where methylation at evolutionarily conserved arginine 452 is required for oxaliplatin resistance. Functional validation demonstrated that IGF2BP1 stabilizes HEG1 mRNA via m6A-dependent mechanisms, forming a PRMT3-IGF2BP1-HEG1 signaling axis. HEG1 knockdown abrogated both cell proliferation and drug resistance, whereas HEG1 overexpression rescued these phenotypes.

In glioblastoma (GBM), PRMT3-mediated stabilization of HIF1α drives angiogenesis and glycolysis under hypoxic conditions (13). High PRMT3 expression correlates with glioma malignancy and poor prognosis, positioning it as a therapeutic target. In colorectal cancer, PRMT3 promotes tumorigenesis through dual mechanisms whereby it stabilizes HIF1α and METTL14 in a methylation-dependent manner, thereby enhancing glycolysis, angiogenesis, and inflammation (16, 17). Targeting the PRMT3-HIF1α axis through pharmacological inhibitors or methylation-blocking peptides may overcome anti-angiogenic resistance in colorectal cancer (Figure 3).

The innate immune system serves as the first line of defense against viral pathogens, employing a variety of mechanisms to recognize and neutralize threats. Among these, the antiviral innate immunity is paramount for the detection of viral nucleic acids and the subsequent activation of immune responses. This initial immune response is critical for controlling viral infections and preventing disease progression. PRMT3’s role extends beyond target protein methylation to include regulation of key inflammatory pathways such as cGAS/STING and NF-κB. The cyclic cGAS and STING pathway are vital for sensing cytosolic DNA and initiating type I interferon responses. PRMT3 has been implicated in modulating this pathway by methylating proteins involved in cGAS/STING signaling, potentially influencing the activation of downstream interferon responses and pro-inflammatory signaling. By affecting this pathway, PRMT3 can amplify the immune response during infections or cellular stress, but it can also contribute to autoimmune inflammation when dysregulated. NF-κB is a key transcription factor in regulating immune responses and inflammation. PRMT3 can impact the NF-κB signaling pathway by methylating either NF-κB subunits directly or regulatory proteins that modulate its activity. The methylation status of these proteins can either promote or inhibit NF-κB activation, thereby influencing the expression of pro-inflammatory cytokines.

In addition to the cGAS/STING pathway, PRMT3 also modulates NF-κB signaling, a critical transcription factor that regulates inflammatory responses. The NF-κB pathway is activated in response to various stimuli, including pro-inflammatory cytokines and pathogen-associated molecular patterns. Upon activation, NF-κB translocates to the nucleus and drives the expression of numerous pro-inflammatory genes, which are essential for orchestrating an effective immune response. PRMT3 can influence NF-κB signaling by methylating its subunits or regulatory proteins that affect its activity. The methylation status of these proteins can either promote or inhibit NF-κB activation, thereby modulating the expression of key inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Dysregulated NF-κB activity can lead to chronic inflammation, tissue damage, and contribute to the pathogenesis of autoimmune diseases (37). By negatively regulating this pathway, PRMT3 adds another layer of complexity to its role in modulating antiviral immunity. Given that NF-κB is a critical mediator of inflammation, PRMT3’s ability to regulate this pathway underscores its role in inflammatory diseases.

Antiviral innate immunity operates through the recognition of pathogenic nucleic acids by pattern recognition receptors. These receptors, including retinoic acid-inducible gene I (RIG-I) and cGAS, play crucial roles in detecting viral RNA and DNA, respectively. Upon recognition of viral components, these pattern recognition receptors initiate a cascade of signaling events that lead to the production of type I interferons and inflammatory cytokines. This cascade activates hundreds of antiviral effector proteins, including MX1 and OAS (47), which form a robust antiviral network that effectively counters viral replication and spread. The cGAS/STING pathway is critical for the detection of cytosolic DNA and the subsequent induction of interferon responses. When cGAS detects viral DNA within the cytoplasm, it catalyzes the synthesis of cyclic GMP-AMP, a second messenger that binds to and activates STING, an endoplasmic reticulum-localized protein. Activated STING translocates to the Golgi apparatus, leading to the recruitment of TANK-binding kinase 1 and the subsequent phosphorylation of interferon regulatory factor 3 (48). Phosphorylated interferon regulatory factor 3 dimerizes and translocates to the nucleus to initiate the transcription of type I interferons and other pro-inflammatory genes. This pathway is crucial for mounting an effective immune response to viral infections; however, the activation of the cGAS/STING pathway must be tightly regulated to prevent uncontrolled inflammation and tissue damage. Dysregulation of this signaling cascade can lead to chronic viral persistence and autoimmune diseases, marking the importance of mechanisms that finely tune antiviral responses.

Notably, the preferential modification of pattern recognition receptors by PRMT3 during viral infection is primarily driven by the coordinated regulation of substrate availability and the post-translational modification of PRMT3 itself. On one hand, viruses activate the Toll-like receptor/retinoic acid-inducible gene I-like receptor signaling pathway via pathogen-associated molecular patterns, which significantly induces the transcription and translation of RNA/DNA sensors such as cGAS and RIG-I. These sensors harbor abundant arginine-glycine domains in their molecular structures, which form stable hydrogen bonds with the hydrophobic pocket of PRMT3’s N-terminal C₂H₂ zinc finger domain. This designates the sensors as preferred substrates for PRMT3, allowing PRMT3 to bind them before metabolism-related substrates like LXRα or HIF-1α. On the other hand, virus-induced secretion of interferon-γ activates JAK1/2 kinases, which further phosphorylate PRMT3’s Tyr85 residue, increasing the zinc finger domain’s binding affinity for PRRs by approximately 2-fold. Meanwhile, viral infection also induces cellular expression of metallothioneins, which chelate cytoplasmic Zn²⁺ to restrict excessive PRMT3 activation. This forms a negative feedback loop in which PRMT3 inhibits antiviral signaling and MTs restrict PRMT3 activity, and this loop balances the intensity of immune suppression (49).

Antiviral innate immunity constitutes the host’s initial defense against viral pathogens. Pattern recognition receptors detect viral nucleic acids, triggering type I interferon (IFN-α/β) production and inflammatory cytokine release. RIG-I is instrumental in the recognition of viral RNA, and its activation leads to the induction of pro-inflammatory cytokines and type I interferons (50, 51). However, PRMT3-mediated methylation at R730 disrupts RIG-I oligomerization, a crucial step for its activation. When RIG-I fails to oligomerize properly, it is unable to effectively bind viral RNA, leading to a reduced interferon response. The consequence is a diminished antiviral state within the cell, facilitating viral replication and persistence. Similarly, MDA5, another key PRR that recognizes long double-stranded viral RNA, is also impacted by PRMT3 through methylation at R822. The perturbation of MDA5 activity through this modification interferes with its capability to form filamentous structures necessary for signal transduction, thereby attenuating the cytoplasmic signaling required for effective interferon production. This can contribute to viral immune evasion and may play a role in the pathogenesis of chronic viral infections. This activates hundreds of antiviral effector proteins including MX1 and OAS, which collectively form a broad-spectrum antiviral network. Key features include rapid activation, immune surveillance, and adjuvant roles in adaptive immunity via antigen presentation and co-stimulation. Dysregulation of this system contributes to chronic viral persistence, cytokine storms, and tumor immune evasion. Epigenetic regulators like PRMTs have emerged as critical nodes in antiviral defense, offering novel therapeutic opportunities.

cGAS serves as a sentinel for cytosolic DNA, and its activation leads to robust innate immune responses (52). By methylating cGAS at R111, PRMT3 inhibits its ability to bind DNA, thereby blunting the activation of the cGAS/STING pathway. This disruption not only dampens interferon production but also alters the expression of other pro-inflammatory mediators. The reduced activation of the cGAS/STING pathway means that the innate immune system’s ability to sense and respond to viral DNA is significantly impaired, thus fostering an environment conducive to viral persistence. PRMT3 negatively modulates antiviral responses by catalyzing asymmetric arginine dimethylation at R730 of RIG-I, R822 of MDA5, and R111 of cGAS (49). This post-translational modification disrupts receptor oligomerization and downstream interferon signaling, thereby attenuating nucleic acid binding and antiviral effector activation. This mechanism likely exacerbates chronic viral pathogenesis by blunting interferon responses, providing mechanistic insights into viral immune evasion and potential targets for therapeutic intervention.

PRMT3 plays a multifaceted role in regulating immune responses and maintaining mitochondrial integrity, and its dual functionality makes it a compelling subject for therapeutic exploration in cancer, particularly in immune evasion and pro-inflammatory signaling. One of the critical functions of PRMT3 lies in its ability to methylate HSP60 (53), a chaperone protein that is vital for maintaining mitochondrial function and integrity. Methylation of HSP60 by PRMT3 stabilizes its oligomeric state, thereby ensuring proper protein folding and facilitating mitochondrial protein quality control. This stabilization is essential not only for mitochondrial health but also for the immune response, particularly regarding the cGAS/STING pathway, which plays a vital role in sensing cytosolic DNA and initiating an antiviral response.

When PRMT3 methylates HSP60, it effectively suppresses the cGAS/STING activation pathway. This suppression can have significant implications in the context of cancer. Tumor cells often utilize mechanisms to evade immune detection, and the inhibition of the cGAS/STING pathway is one such strategy (54). By keeping this pathway in check, PRMT3 may allow tumors to escape immune surveillance, promoting an environment conducive to tumor growth and metastasis. Conversely, the application of PRMT3 inhibitors has been shown to reverse this suppression, leading to the activation of the cGAS/STING-dependent antitumor immunity. This crucial discovery positions PRMT3 not only as a biomarker for predicting responses to immunotherapy but also as a promising therapeutic target in the treatment of malignancies, such as hepatocellular carcinoma. Paradoxically, PRMT3 maintains mitochondrial integrity by methylating HSP60, which stabilizes its oligomeric state and suppresses cGAS/STING activation. PRMT3 inhibitors reverse this effect, activating cGAS/STING-dependent antitumor immunity (37). This dual functionality positions PRMT3 as a biomarker for predicting immunotherapy response and a therapeutic target in hepatocellular carcinoma.

In colorectal cancer, PRMT3 promotes immune evasion through c-MYC stabilization. By inhibiting c-MYC ubiquitination, PRMT3 enhances oncoprotein stability and downstream pro-tumorigenic signaling (55). These context-dependent roles highlight PRMT3’s functional plasticity, likely arising from differential substrate availability and post-translational modifications in distinct microenvironments (Figure 3). In the context of colorectal cancer, PRMT3’s role in promoting immune evasion becomes even more pronounced. One of the critical mechanisms is the stabilization of the oncogene c-MYC. c-MYC is a well-established transcription factor that regulates various cellular processes, including cell proliferation, metabolism, and apoptosis. In cancer, its overexpression is associated with increased tumor aggressiveness and poor patient outcomes (56). PRMT3 contributes to the stability of c-MYC by specifically inhibiting its ubiquitination, a post-translational modification that typically marks proteins for degradation by the proteasome. By preventing the ubiquitination of c-MYC, PRMT3 enhances the stability of this oncoprotein, leading to the persistent activation of downstream signaling pathways that favor tumorigenesis. These pathways often promote cell proliferation, enhance metabolic processes favoring tumor growth, and facilitate immune suppression. The interplay between PRMT3 and c-MYC exemplifies the complex regulatory networks in tumor microenvironments, where PRMT3 orchestrates pro-tumorigenic signaling. Additionally, c-MYC has been shown to regulate the expression of various immune checkpoints and suppress immune-related gene transcription, further facilitating immune evasion (57, 58). Thus, PRMT3’s role in stabilizing c-MYC creates a feedback loop that not only promotes tumor growth but also inhibits effective anti-tumor immune responses.

The preferential selection and efficient modification of oncogenic substrates by PRMT3 in the tumor microenvironment are mainly driven by the dual regulation of substrate availability and the post-translational modification of PRMT3 itself. From the substrate standpoint, either MYC activation or HIF-1α stabilization in tumor cells markedly upregulates the expression of oncogenic substrates such as HIF-1α and METTL14. The Arg residues of these substrates are surrounded by hydrophilic Ser/Thr amino acids, which form additional salt bridges with the Asp/Glu residues in PRMT3’s N-terminal zinc finger domain. Their binding affinity for PRMT3 is far greater than that of HSP60, enabling PRMT3 to preferentially modify oncogenic substrates (16). From the perspective of PRMT3 self-regulation, the abnormally activated PI3K-AKT pathway in tumors phosphorylates the Ser201 residue near PRMT3’s catalytic domain, directly enhancing its catalytic efficiency for substrates like HIF-1α and METTL14. Furthermore, p53 mutations in most tumors reduce the expression of its target gene MDM2, leading to decreased K48-linked ubiquitination of PRMT3. Consequently, PRMT3’s half-life is prolonged from 4 hours to 8 hours, providing an ample temporal window for its sustained modification of oncogenic substrates (14, 17).

The functional plasticity exhibited by PRMT3 underscores the importance of the tumor microenvironment in determining its roles and effects. This plasticity likely arises from differential substrate availability and variations in post-translational modifications that occur in response to specific microenvironmental signals. For instance, the availability of different target substrates may shift depending on the cellular context, whether it be in a pro-inflammatory or immunosuppressive microenvironment. In inflammatory conditions, cGAS/STING pathway activation can be beneficial for eliminating tumor cells, and PRMT3’s suppression of this pathway may represent a protective mechanism that cancer cells exploit. Conversely, in a microenvironment characterized by heightened immune pressure, PRMT3 may pivot toward enhancing immune evasion strategies through c-MYC stabilization or other tumor-promoting pathways. This duality illustrates that PRMT3’s influence is not static but rather responsive to external cues within the tumor microenvironment.

PRMT3 regulates tissue injury and fibrosis primarily through mediating the ADMA-NO axis signaling pathway. PRMT3 catalyzes the conversion of substrate arginine to ADMA in two sequential steps, relying on the dual E-loop and His254/Asp256 proton transfer system within its C-terminal catalytic domain. It firstly converts arginine to MMA, followed by further conversion of MMA to ADMA. Additionally, its N-terminal C₂H₂ zinc finger domain preferentially recognizes ADMA precursor proteins containing the “Arg-Gly-Gly motif”, ensuring substrate specificity for ADMA synthesis.

This pathway exhibits a positive feedback loop of ADMA→PRMT3→ADMA. ADMA upregulates the transcriptional and protein expression of PRMT3, which in turn further promotes ADMA synthesis, forming a vicious cycle that exacerbates NO inhibition (59). ADMA inhibits NO through two distinct mechanisms. Firstly, it competitively binds to the active site of NOS, directly blocking NOS-mediated conversion of L-arginine to NO. Secondly, it induces NOS uncoupling, which prevents NOS from generating NO normally and instead triggers the production of ROS. Ultimately, this leads to reduced NO bioavailability and the loss of NO’s tissue-protective effects (42, 60).

CKD affecting 10%-13% of the global population (61), poses a significant public health challenge. Tubulointerstitial fibrosis represents the common pathological pathway for diverse renal disorders progressing to end-stage kidney disease. PRMTs epigenetic regulators critical for cellular homeostasis, have been implicated in renal protection through type I PRMTs. PRMT3, a type I PRMT, plays a key role in ADMA biosynthesis. ADMA, primarily cleared by renal excretion, accumulates in chronic renal failure patients (62), where plasma levels correlate with disease progression. Mechanistically, PRMT3-mediated ADMA accumulation alleviates tubulointerstitial fibrosis (18). Notably, ADMA serves as a biomarker for endothelial dysfunction and inflammation. In coronary artery disease (60), PRMT3 expression positively correlates with myocardial ADMA levels. Elevated ADMA in coronary endothelial cells upregulates PRMT3 expression, which inhibits nitric oxide synthase, thereby increasing atherosclerotic risk (63).

Animal models and clinical evidence further validate the role of the PRMT3-ADMA axis in renal fibrosis. In a mouse model of unilateral ureteral obstruction, PRMT3 mRNA and protein levels were significantly upregulated in the obstructed kidneys. In contrast, following PRMT3 gene knockout, renal tissue ADMA levels decreased rather than increased, accompanied by a significant rise in collagen deposition. Exogenous injection of ADMA reversed the aggravated fibrotic phenotype in PRMT3-knockout mice, directly confirming that ADMA acts as a downstream effector molecule of PRMT3 in suppressing renal fibrosis (18). In clinical samples, PRMT3 expression in renal tissues of patients with CKD was positively correlated with ADMA levels. Moreover, as a well-recognized marker of endothelial dysfunction, ADMA reduces NO production by inhibiting NOS activity (64). This moderate NO inhibition effect prevents excessive NO-mediated renal tubular injury and exacerbated fibrosis, providing a rational basis for targeting this axis in anti-fibrotic therapy for CKD (65).

CKD is characterized by irreversible progression and cardiovascular complications, with vascular calcification emerging as a critical mediator (66). Osteoblastic transdifferentiation of VSMCs underlies this process, which is linked to glycolytic reprogramming (67). HIF-1α is a critical transcription factor that responds to cellular oxygen levels and plays a crucial role in the adaptation to hypoxia (68). Under inflammatory conditions, PRMT3 has been shown to methylate HIF-1α, which enhances its stability and transcriptional activity. When HIF-1α is methylated, it promotes the expression of genes involved in angiogenesis, glucose metabolism, and pro-inflammatory cytokine production. This methylation process is crucial during inflammation, as it not only helps cells adapt to low oxygen conditions but also perpetuates the inflammatory response. Zhou et al. (8)demonstrated PRMT3 upregulation in CKD-affected medial VSMCs and β-glycerophosphate-induced calcification models. PRMT3 promotes glycolysis through HIF-1α methylation, exacerbating CKD-associated vascular calcification and inflammatory responses.

In recurrent miscarriage (RM) models, macrophage PRMT3 downregulation reduces NO bioavailability, inducing trophoblast apoptosis and perturbing maternal-fetal interface function, suggesting PRMT3 involvement in pregnancy-related inflammation (Figure 3). LXRa is a nuclear receptor that regulates lipid metabolism and inflammation. PRMT3 mediates the methylation of LXRa, affecting its transcriptional activity. Methylation of LXRa can modulate the receptor’s interaction with coactivators and corepressors, thus impacting its ability to regulate genes involved in lipid homeostasis and inflammation. In the context of inflammatory diseases, the altered function of LXRa due to PRMT3 activity can contribute to dysregulated lipid metabolism, which is often associated with chronic inflammation. ADMA is an endogenous inhibitor of nitric oxide synthase, which plays a vital role in maintaining vascular health. PRMT3 alters the levels of ADMA by methylating specific proteins involved in its synthesis and degradation. Elevated levels of ADMA can lead to reduced nitric oxide production, promoting vascular dysfunction and inflammation. By modulating ADMA levels, PRMT3 influences nitric oxide signaling pathways that are crucial for maintaining vascular tone and inflammatory responses.

In RM, abnormal activation of the PRMT3-ADMA-NO axis represents a key pathological mechanism. PRMT3 is specifically overexpressed in decidual macrophages of RM patients, where it catalyzes ADMA production by acting on substrates containing the RGG motif. ADMA then competitively binds to the active site of NOS, significantly reducing NO synthesis in decidual tissue. NO deficiency subsequently activates the Fas/FasL pathway, inducing the activation of Caspase-3/7/9 and ultimately leading to trophoblast cell apoptosis, which disrupts the homeostasis of the maternal-fetal interface. Functional validation showed that SGC707, a PRMT3 inhibitor, reduced ADMA levels in macrophages of RM model mice, restored NO concentrations, and decreased embryo resorption rates (11). These findings confirm that targeting the PRMT3-ADMA-NO axis can improve pregnancy outcomes, offering a novel direction for RM treatment.