As a lysine methyltransferase containing SET and MYND domains, Smyd1 plays a crucial role in the development and functional maintenance of the cardiovascular system, with its abnormalities being closely linked to various cardiovascular diseases. Smyd1 generates two isoforms, Smyd1_tv1 and Smyd1_tv2, through alternative splicing (Xu et al., 2024). Among these, Smyd1_tv1 is predominantly expressed in the myocardium and is essential for sarcomere organization in cardiomyocytes and cardiac function, whereas Smyd1_tv2 is mainly localized in skeletal muscle and is dispensable for cardiac development (Xu et al., 2024). By localizing to the sarcomeric M-line and enhancing its binding to myosin chaperone proteins (such as Hsp90α1 and Unc45b), Smyd1_tv1 maintains sarcomeric integrity and normal mitochondrial organization in cardiomyocytes. Its deficiency leads to cardiac hypertrophy, sarcomeric disarray, and cardiac dysfunction. In contrast, zebrafish expressing only Smyd1_tv2 die during the larval stage due to cardiac defects (Xu et al., 2024).

Smyd1b deficiency impairs the recruitment and integration of secondary heart field progenitor cells, leading to failure of cardiac looping, expansion of cardiac jelly, and downregulation of key transcription factors such as gata4, gata5, and nkx2.5, thereby triggering congenital heart defects (Prill et al., 2025). In myocardial ischemic injury, overexpression of Smyd1a upregulates OPA1 expression, promoting mitochondrial cristae remodeling and the formation of respiratory chain supercomplexes. This process enhances mitochondrial respiratory efficiency, reduces infarct size, and decreases cardiomyocyte apoptosis, ultimately exerting a cardioprotective effect on cardiac function. Notably, Smyd1 expression is downregulated in the myocardium of patients with heart failure, whereas it remains at normal levels in control patients, highlighting its importance in myocardial repair (Szulik et al., 2023).

Furthermore, Smyd1 regulates sarcomere assembly and homeostasis by monomethylating lysine 35 (K35) on myosin heavy chain (MyHC). Loss of this modification leads to the degradation of MyHC via the ubiquitin-proteasome system, resulting in sarcomeric defects in both cardiac and skeletal muscles. This regulatory mechanism is conserved in human-induced pluripotent stem cell-derived cardiomyocytes (Diofano et al., 2025). Smyd1 also directly interacts with CHD4 to cooperatively repress gene programs related to glycolysis, hypoxic response, and angiogenesis, which is critical for maintaining normal cardiac development (Shi et al., 2024).

Mutations in the human SMYD1 gene are associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and biventricular heart failure, further confirming that abnormalities in Smyd1 are a critical pathogenic factor in cardiovascular diseases (Jiao et al., 2021).

SMYD1, a member of the SMYD protein family with specific HMT activity, exhibits tumor-suppressive characteristics in various malignant tumors, including hepatocellular carcinoma (HCC), gastric cancer (GC), breast cancer (BC), and rhabdomyosarcoma (RMS) (Figure 1).

In HCC, SMYD1 has been identified as a potential tumor suppressor gene. Its expression is transcriptionally repressed by hepatoma-derived growth factor (HDGF). The mechanism involves HDGF recognizing and binding to the promoter region of the SMYD1 gene via its N-terminal PWWP domain, recruiting a transcriptional repressor complex, and leading to SMYD1 transcriptional silencing (Chen et al., 2018). Studies have shown that while the C-terminal 140-amino acid domain (C140) of HDGF does not directly bind to DNA, it significantly enhances the binding affinity of the PWWP domain to chromatin through conformational changes, resulting in an approximately 10-fold increase in the inhibitory efficiency of full-length HDGF compared to the PWWP domain alone (Chen et al., 2018). Functionally, downregulation of SMYD1 disrupts the transcriptional regulatory network of its downstream genes involved in the cell cycle and apoptosis, promoting proliferation, invasion, and metastasis in HCC cells (Yang and Everett, 2007; Yang and Everett, 2009). Additionally, the phosphorylation of serine 103 (S103) in HDGF is crucial for its ability to drive the malignant phenotype of HCC. Mutation of this site (S103A) does not affect its binding to the SMYD1 promoter but abrogates the oncogenic potential of HDGF, suggesting an auxiliary oncogenic mechanism independent of SMYD1 binding (Everett et al., 2011).

In GC, multiple studies have consistently demonstrated that the mRNA and protein expression levels of SMYD1 in GC tissues are significantly lower than in adjacent normal tissues, indicating its potential role as a tumor suppressor. Low SMYD1 expression is significantly associated with shorter overall survival (OS) and progression-free survival (PFS) in patients and serves as an independent risk factor for poor prognosis (Liu et al., 2023). At the molecular pathological level, SMYD1 expression correlates with the clinical stage of GC and is higher in patients with wild-type TP53, suggesting a potential interaction with the p53 signaling pathway (Liu et al., 2021). In the tumor microenvironment, SMYD1 expression is positively correlated with immune infiltration levels of CD4⁺ T cells, macrophages, and dendritic cells, and negatively correlated with tumor mutational burden (TMB), indicating that SMYD1 may affect the progression of GC by regulating anti-tumor immune responses (Liu et al., 2023). Its regulatory mechanism also extends to the epigenetic level; for example, the long non-coding RNA HAND2-AS1 can indirectly upregulate SMYD1 expression through the ceRNA mechanism, participating in the inhibitory pathway of GC (Liu et al., 2021).

In BC, SMYD1 also demonstrates distinct tumor-suppressive properties. Multiple bioinformatics analyses and experimental validations have shown that SMYD1 mRNA is consistently downregulated in various BC subtypes, including medullary carcinoma, ductal carcinoma, and lobular carcinoma, compared to normal breast tissues. This suggests that its inactivation is a common event in BC initiation (Song et al., 2019; Curtis et al., 2012). Patients with high SMYD1 mRNA expression exhibit significantly prolonged recurrence-free survival (RFS), with a hazard ratio (HR) of 0.73, indicating that SMYD1 may serve as a protective factor in BC (Györffy et al., 2010).

Regarding the regulatory mechanism, similar to HCC, SMYD1 expression in BC is inhibited by the oncogenic factor HDGF, suggesting a common regulatory axis across different cancer types (Chen et al., 2012). Notably, the mutation rate of the SMYD1 gene in BC samples is extremely low (approximately 3%), indicating that its downregulation is primarily driven by transcriptional and epigenetic mechanisms, rather than genetic mutations in its coding region (Gao et al., 2013; Cerami et al., 2012). During RMS differentiation, SMYD1 has also been identified as a key regulatory factor. As a muscle-specific HMT, SMYD1 is typically downregulated in RMS cells, and the restoration of its expression is closely linked to myogenic differentiation (Berkholz et al., 2024). miR-206 can promote RMS cell differentiation into mature myocytes by upregulating SMYD1 expression, which induces the expression of muscle-specific genes (e.g., Myogenin, MHC, MCK). While the loss of SMYD1 does not affect miR-206-mediated inhibition of proliferation, its expression is critical for the complete execution of the myogenic differentiation program. Additionally, SMYD1 is localized in both the nucleus and cytoplasm and may play a role in myofibrillogenesis by regulating the folding and assembly of sarcomeric proteins (Coda et al., 2015). Therefore, SMYD1 not only plays a pivotal role in the epigenetic reprogramming of RMS but may also serve as a potential therapeutic target for differentiation-inducing therapies.

Recent studies have revealed an unexpected yet pivotal regulatory role of SMYD1 as a transcription factor in neurodegenerative diseases. Gene expression analysis in C2C12 myoblasts showed that following SMYD1 knockdown, transcripts associated with Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD)—including COX isoforms, NDUFA isoforms, ATPase isoforms, and the microtubule-associated protein Tau/MAPT—were significantly altered (Warren et al., 2018). Further investigations confirmed that SMYD1 and the transcription factor skNAC are co-expressed in the corticostriatal regions of both human and mouse brains, forming a heterodimeric complex in the subcortical regions of transgenic mouse models of AD, PD, and HD (Mayfield et al., 2020). These findings suggest that SMYD1 and skNAC may synergistically regulate neuro-related genes.

In experiments involving the reprogramming of C2C12 myoblasts into neurons, SMYD1 was identified as a rate-limiting factor in this differentiation process (Mayfield et al., 2020). Depletion of SMYD1 impaired the acquisition of neuronal phenotypes and significantly reduced dendritic density, while knockdown of skNAC had no such effect. Mechanistically, SMYD1 regulates key molecules involved in mitochondrial oxidative phosphorylation (e.g., subunits of Complex I and Complex IV), endoplasmic reticulum stress-related factors (e.g., ATF6), and Tau protein, contributing to essential neuronal processes such as energy metabolism and protein homeostasis. Dysfunction of SMYD1 may accelerate pathological changes, including mitochondrial dysfunction and abnormal protein aggregation, thus promoting the onset and progression of neurodegenerative diseases (Mayfield et al., 2020). The expression characteristics and potential role of SMYD1 in ischemic stroke have also been preliminarily explored. In a rat model of ischemic stroke induced by middle cerebral artery occlusion (MCAO), transcriptome sequencing and qRT-PCR validation revealed that SMYD1 mRNA expression was significantly downregulated in the brains of model rats compared to the sham-operated group, indicating that abnormal SMYD1 expression may be linked to the pathological progression of ischemic stroke (Ye et al., 2022). As a key regulatory gene involved in muscle differentiation and remodeling, Smyd1 plays an important role in the pathological mechanisms, treatment, and repair of stress urinary incontinence (SUI) (Fang et al., 2025). The core pathological features of SUI include urethral sphincter muscle fiber injury, neuromuscular atrophy, and urethral closure dysfunction, with insufficient muscle regeneration capacity being a critical factor in the persistence and recurrence of symptoms. Upregulation of Smyd1 directly promotes myogenic regeneration of the urethral sphincter, with its mechanism involving regulation of myofiber differentiation, stabilization of the myocyte cytoskeleton, and inhibition of proteolysis.

In SUI therapeutic strategies based on regenerative medicine, a thermosensitive hydrogel system containing leucine and decellularized extracellular matrix (dECM) has been shown to significantly upregulate Smyd1 expression by activating the mTOR signaling pathway. This system synergizes with muscle regeneration markers such as Myoz1, improving the structural integrity and contractile function of the urethral sphincter. In a female rat model of SUI, a composite injection system loaded with ZIF-8/PEG200@Mg nanoparticles for pretreating adipose-derived mesenchymal stem cells (ADSCs) achieved synchronous regeneration of both striated and smooth muscle fibers through sustained high expression of Smyd1. Simultaneously, it promoted the stability of neuromuscular junctions (NMJ), significantly increased leak point pressure (LPP), and restored urethral closure function. These findings confirm that targeted regulation of Smyd1 is a key mechanism for enhancing defective muscle regeneration of the urethral sphincter in SUI, providing molecular targets and experimental evidence for the development of novel SUI therapeutic regimens that simultaneously promote muscle regeneration and nerve repair (Fang et al., 2025).

To date, specific inhibitors targeting SMYD1 have not been successfully developed. However, accumulating evidence suggests that small-molecule compounds or therapeutic agents can modulate SMYD1-related signaling pathways, indirectly ameliorating pathological conditions associated with SMYD1 dysfunction. Preliminary investigations have also explored the regulatory effects of certain drugs on SMYD1. In the field of cardiac differentiation, Chang et al. (2024) reported that insulin and insulin-like growth factor 1 (IGF-1) effectively enhance cardiomyocyte differentiation efficiency in SMYD1-knockout cells. The underlying mechanism involves the reduction of p-ERK expression, a downstream molecule in SMYD1-deficient cells, rescuing cardiomyocyte differentiation defects. This finding highlights a potential molecular target for intervening in SMYD1 dysfunction-associated cardiac diseases.

Additionally, doxorubicin (DOX), an anthracycline drug commonly used in cancer treatment, was found to upregulate SMYD1 expression in human pluripotent stem cell-derived ventricular cardiomyocytes within 3D engineered cardiac tissues (Shamloul et al., 2021). SMYD1 overexpression subsequently regulates multiple critical processes, including cardiac gene expression, contractile function, calcium handling, and electrophysiological function. However, the dose-dependent cardiotoxicity of DOX limits its direct application in the treatment of SMYD1-related cardiac diseases.

In the broader context of SMYD family inhibitor research, several agents have been developed, such as AZ50552 targeting SMYD2 and BCI-121 targeting SMYD3. However, these inhibitors lack specific regulatory effects on SMYD1. Currently, research on SMYD1 is primarily focused on elucidating its biological functions and associated signaling pathways. No dedicated SMYD1 inhibitors have entered the development phase or clinical trials. The development of SMYD1-specific inhibitors will depend on further insights into its molecular structure and mechanism of action (P et al., 2023).