It has been reported that Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant cardiomyopathy (100) characterized by cardiomyocyte replacement with fibro-adipose tissues, resulting in abnormal Excitation-Contraction (EC) coupling and a series of malignant events such as Ventricular Arrhythmias (VA), HF, and Sudden Cardiac Death (SCD) (101, 102). The disease is considered a major cause of sudden death in young adults, especially athletes (6, 103), and its prevalence is estimated to be between 1/2,500 and 1/5,000, with a male predominance (female to male ratio of 1:2.7), which may be related to the disease genes and androgens (104, 105).

Intercalated disks (connective structures between cardiomyocytes) are the functional unit that provides the mechanical and/or electrical coupling that enables the coordinated and synchronized contraction of cardiomyocytes. According to research, variants affecting the gene encoding the desmosomal protein are responsible for approximately 50%–60% of ARVC cases (106). Five of the eight genes that account for pathogenic or potentially pathogenic variants are desmosomal genes (107). The primary function of “glue” desmosomes is transmitting mechanical strength between myocardial cells. When the desmosomes are mutated, the myocardium undergoes cell detachment and death, later replaced by fibro-adipose tissues, thereby resulting in scarring, wall thinning, and aneurysms. This adhesion defect is exacerbated by exercise, with a greater impact on the thinner right ventricle (55, 108). Li et al. (58) identified a novel heterozygous mutation in the KLF15 gene in a family with atrial fibrillation (AF), ventricular arrhythmia, and hypertrophic cardiomyopathy. Subsequent investigations revealed that the loss-of-function mutation in KLF15 could potentially trigger AF by disrupting myocardial energy metabolism (59). Moreover, this mutation could exacerbate AF by prolonging repolarization and extending the effective refractory period (60, 109).

Plakophilin-2 (PKP2) mutations are the most widespread genetic association in ARVC. Khudiakov et al. (56) obtained an iPSC line carrying 2 mutations in the PKP2 gene from a 14-year-old female with severe ARVC, and detected high OCT4, NANOG, and SOX2 mRNA levels after reprogramming and transducing them with Sendai virus vectors, confirming the pluripotency of the iPSC line. Yang et al. (75) used a similar approach to transduce PBMCs carrying three reprogramming factors (KOS, KLF4, and cMYC) obtained from a 41-year-old female ARVC patient. The iPSCs obtained exhibited pluripotency marker expression, intact karyotype, and the potential to differentiate into multiple germ layers. Similarly, KLF4 produces iPSCs via reprogramming in DCM (110, 111). Drawing on KLF4's pivotal role in regulating cardiac potassium (K⁺) channels, Chowdhury et al. (57) established a connection between mitogen-activated kinase kinase-7 (MKK7) deficiency and heightened susceptibility to arrhythmia. MKK7 deficiency prevents the phosphorylation of histone deacetylase-2, leading to the accumulation of filamentin A in the nucleus. This filamentin A then forms a complex with KLF4, causing KLF4 to dissociate from the promoter regions of several potassium channel genes. Consequently, this disrupts transcription levels, delays repolarization, and ultimately precipitates ventricular arrhythmia.

Diabetic Cardiovascular Diseases (DCVDs) account for over 50% of diabetes-related mortalities (112), including diabetic cardiomyopathy (a specific type of heart disease) cases (113, 114). The existence of a specific diabetic heart muscle disease that does not involve CAD or HTN was first proposed by Lundbaek in 1954 (115, 116). In 2008, the European Society of Cardiology (ESC) defined the disease as an abnormality of the heart muscle in terms of its structure and function, along with the absence of CADs, HTN, and valvular and congenital heart diseases sufficient to cause the observed myocardial abnormality (5). Nevertheless, the ESC stated again in 2018 that there was no definition of diabetic cardiomyopathy (117). Given the lack of consensus on its definition, it remains difficult to accurately assess epidemiologic data on diabetic cardiomyopathy-related morbidity and mortality. However, clinical trials in Type 2 Diabetes Mellitus (T2DM) patients revealed an HF prevalence of 10%–30% (117).

Diabetic cardiomyopathy is a major risk factor for diabetes-related morbidity and mortality. It is characterized by hypoinsulinemia and hyperglycemia in Type 1 Diabetes Mellitus (T1DM) patients and hyperinsulinemia or insulin resistance in T2DM patients (118). Although the underlying mechanism of some KLFs in diabetes remains unclear (44), studies have acknowledged the essential role KLFs play in many types of diabetes (71, 89, 119–124) (Table 3). For example, it was reported that KLF7 can regulate insulin sensitivity and susceptibility to type 2 diabetes by lowering adiponectin and leptin levels (126, 127), and can negatively regulate miR-132-3p to aggravate the transition of Human Umbilical Vein Endothelial Cells (HUVECs) to a mesenchymal state after high glucose exposure (128). Similarly, KLF14 has been implicated in increasing susceptibility to type 2 diabetes by regulating key genes associated with insulin resistance (122, 123). For instance, the risk alleles G of rs972283 and rs4731702 have been linked to this effect. Additionally, KLF11 plays a negative regulatory role in NDM, Maturity Onset Diabetes in Young (MODY) (129, 132), as well as T2DM (130) and Type 1B Diabetes (131). Mutations in KLF11 may hinder insulin secretion in pancreatic β-cells by inhibiting insulin promoter regulatory activity, consequently impairing insulin gene transcription in NDM and MODY. Moreover, KLF11 is involved in regulating hepatic glucose metabolism. Zhang et al. (130) found that overexpression of KLF11 in mouse hepatocytes inhibited the expression of gluconeogenic genes, such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and phosphoenolpyruvate carboxykinase (PEPCK-C), thereby reducing cellular glucose output. As a negative regulator of adipogenesis, KLF2 is highly expressed in preadipocytes and regulates glucolipid metabolism and insulin sensitivity by directly inhibiting the PPARγ2 promoter activity (119). Furthermore, although KLFs 2, 4, and 9 have been strongly associated with Gestational Diabetes Mellitus (GDM) development, the specific regulatory roles of KLFs 2 and 4 remain unclear, necessitating additional research in a larger patient population (121, 125). Research indicates that KLF9 plays a crucial role in regulating hepatic glucose metabolism. Hepatic KLF9 overexpression induced by dexamethasone (Dex) and fasting directly binds to its promoter, stimulating the expression of the PGC-1α gene and activating the gluconeogenesis program. A mutation in KLF9 eliminates the stimulatory effect of Dex on cellular glucose output and effectively attenuates Dex-induced hyperglycemia (120), a critical finding for patients requiring long-term glucocorticoid therapy.

While genetic susceptibility plays a significant role in the pathogenesis of T2DM, the identified genes influencing susceptibility to T2DM are still limited (133, 134). Kanazawa et al. (127) found that KLFs not only play vital roles in cellular differentiation and tissue development but are also implicated in the pathogenesis of T2DM. In their study, they genotyped 33 single nucleotide polymorphisms (SNPs) in 12 KLF genes in T2DM patients and found a direct association between an allele of the SNP site in the second intron of KLF7 and T2DM, suggesting KLF7 as a novel candidate gene for genetic susceptibility to T2DM and its role in promoting the development of diabetic cardiomyopathy. Diabetes mellitus is an independent predictor of left ventricular hypertrophy (LVH), but not all diabetic patients develop LVH, indicating genetic components are involved. A clinical study investigated the association between the KLF15 gene and LVH in T2DM patients. Patel et al. (89) prospectively recruited 318 T2DM patients without known cardiac disease for transthoracic echocardiographic evaluation and genotyping for two KLF15 SNPs (rs9838915 and rs6796325). They found that the A allele of the rs9838915 SNP in the KLF15 gene was associated with increased left ventricular mass in patients, providing more accurate risk stratification for developing HF. Diabetic cardiomyopathy pathophysiology is multifaceted and involves complex metabolic pathways, with the main pathological features being myocardial hypertrophy and fibrosis, inflammation, cellular autophagy and apoptosis, and elevated OS markers (135–137). Myocardial hypertrophy makes the myocardium less compliant, causing diastolic dysfunction, which ultimately results in arrhythmia, HF, and even SCD (138, 139). In these processes, KLFs regulates the upstream and downstream pathways (Figure 4).

Dilated Cardiomyopathy (DCM), a multifactorial disorder associated with genetics, immunity, infection, and the environment, is primarily characterized by heart enlargement and systolic dysfunction (51, 158, 159). The prevalence of DCM is at 1:2,500 in 2013 (160) and the diseases is always progressive, eventually leading to irreversible HF and sudden death. The annual SCD incidence in DCM is 2%–4% (161, 162). Given that the disease is multifactorial, effectively targeting treatment to its etiology has become a major research focus (158, 163, 164). In this regard, multiple studies recently demonstrated the critical functions of KLFs in DCM, including regulating molecular mechanisms contributing to DCM progression.

Multiple mechanisms such as inflammation, Endoplasmic Reticulum Stress (ERS), and mitochondrial dysfunction play vital roles in the DCM-associated ventricular dysfunction progression and HF development. Specifically, it has been reported that myocardial injury triggers an inflammatory response. Zhang et al. (74) found that the KLF2 overexpression-derived Extracellular Vesicles (EVs) reduced cardiac inflammation and improved left ventricular dysfunction in DCM mice by inhibiting Ly6C^high monocyte mobilization via targeting the CCR2 protein. High KLF2 expression in ECs exerts an anti-inflammatory effect, implying that KLF2 may be a potential therapeutic target for DCM treatment.

Furthermore, growing evidence highlights the crucial role of genetic defects in the pathogenic mechanism of DCM (165). As one of the mutation carriers of disease-causing genes, KLF5 mutations co-segregating with DCM have shown complete penetrance in this family, and genetically compromised KLF5 is highly susceptible to DCM (76). Notably, KLF13 is also co-segregated from DCM. Also known as FKLF2/BTEB3/RFLAT-1/RFLAT1/NSLP1, KLF13 is a new DCM susceptibility gene localized on chromosome 15q13.3. Guo et al. (77) conducted sequencing analysis focusing on specific genes within the localization region of human chromosome 15q13.1-q13.3 and identified three mutations that co-segregated with the dilated cardiomyopathy (DCM) phenotype with complete penetrance. These mutations, namely c.430G>T (p.E144X), c.580G>T (p.E194X), and c.595T>C (p.C199R), exhibited impaired transactivation of the target genes ACTC1 and MYH7, both individually and in combination with GATA4, a gene known to induce DCM. Furthermore, these mutations displayed reduced binding capacity to the promoters of ACTC1 and MYH7. Furthermore, the intracellular distribution of E144X mutant KLF13 was disrupted. In summary, detecting the aforementioned new susceptibility genes and loci offers new insights into the DCM molecular pathogenesis and may provide guidance for precision medicine for DCM.

Desmin, a major intermediate filament protein in cardiomyocytes, is a fundamental component of the cellular structure and the Purkinje fibers of the conduction system (166, 167). Desmin is encoded by the DES gene (OMIM *125660), and mutations in this gene are hypothesized to disrupt mechanical stress in the muscle, leading to rhabdomyolysis (168–170) Additionally, desmin is crucial in balancing ROS generation with antioxidant defense. According to research, MnSOD overexpression and/or catalase are the major antioxidant defense systems that can reduce ROS production and improve cardiac function in desmin-deficient mice hearts (171).

Desmin-Related Cardiomyopathy (DRCM) presents early with lower extremity muscle weakness and gait disturbances before progressing to the proximal, respiratory, fascial, and cardiac muscles, eventually leading to arrhythmias and congestive heart failure. Notably, heart defects occasionally precede skeletal muscle defects (167, 172, 173). A meta-analysis of 159 patients with 40 different DES gene mutations revealed that more than 70% of carriers exhibited myopathy or muscular weakness and that about 50% of carriers had cardiomyopathies. In another study, up to 60% of patients had a cardiac conduction disorder or arrhythmias, such as an atrioventricular block (174). Except for symptomatic treatments for alleviating the symptoms, especially in the cardiac area focusing on cardiovascular complications (175, 176), there are currently no targeted therapies for DRCM. Khudiakov et al. (79) delivered four reprogramming factors (OCT4, KLF4, SOX2, and CMYC) with Sendai virus from patient-specific fatty tissue-derived pluripotent Mesenchymal Stromal Cells (MSCs) carrying heterozygous splice site mutations in the DES gene using a non-integrative reprogramming approach, ultimately yielded a human iPSC line. Establishing an iPSC line holds promise for addressing DRCM and for the future development of innovative drugs. Several KLFs may share similar regulatory mechanisms across various muscle tissues. Moreover, within the same muscle tissue, there could be synergistic or antagonistic interactions among KLFs, crucial for muscle tissue development and functional regulation. For instance, KLF2, KLF4, KLF10, and KLF15 have been implicated in these processes. In mouse skeletal muscle cells, the extracellular signal-regulated kinase 5 (ERK5) signaling pathway can induce the upregulation of KLF2 and KLF4 genes via the Sp1 transcription factor. This activation subsequently promotes the expression of nephronectin (Npnt) genes, facilitating skeletal muscle cell fusion through enhanced cell-matrix adhesion (78). KLF15, on the other hand, can stimulate the expression of the slow-twitch fiber gene Myh7 (MHC-β/slow) by targeting the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) gene, thereby positively regulating skeletal muscle differentiation (82). Conversely, KLF10 inhibits myoblast proliferation by suppressing the function of pro-proliferative signaling molecules (80) and the expression of cyclin (81). Most mutations associated with DRCM, such as those affecting CRYAB and BAG3, are missense or small deletion mutations. The formation of aggregates appears to be a significant trigger for DRCM. However, the downstream effects of these mutations are diverse and heterogeneous (177). While a direct link between DRCM and KLFs has yet to be established, ongoing advancements in molecular and cellular biology hold promise for the development of molecular therapies for DRCM. Targeting the regulation of DES gene expression by KLFs may emerge as a promising strategy for reducing the expression of mutant DES alleles and mitigating DRCM pathology.

Hypertrophic Cardiomyopathy (HCM), a relatively common monogenic heart disease with autosomal dominant inheritance, is characterized by ventricular hypertrophy on echocardiography, mostly in the left ventricle (51, 178, 179). The disease was once assumed to be a sudden exercise death disease that primarily affected young men, but is no longer restricted to young males. According to the 2018 global hypertrophic cardiomyopathy burden statistics, HCM affected 6.3 billion people or 88% of the world's population (178). Auspiciously, HCM treatment has progressed from limited palliative pharmacotherapy and occasional high-risk surgery to more definitive screening tools and highly efficient interventional therapies, resulting in a 0.5% annual reduction in morbidity and mortality (180–183).

Although HCM is usually a non-progressive disease, HF symptoms may occur or worsen at any age, most often in middle-aged individuals (184, 185). Efficient management of myocardial hypertrophy is crucial given its potential progression to HF. One significant hallmark of this transition is the shift in myocardial substrate preference from FAO to glycolysis, resembling an embryonic metabolic profile. KLFs have emerged as key transcriptional regulators in pathological cardiac hypertrophy and metabolism. For instance, Wang et al. (86) demonstrated that both cardiac-specific knockdown and overexpression of KLF7 disrupt the balance between glycolysis and fatty acid metabolism, leading to cardiac hypertrophy and myocardial fibrosis. Additionally, KLF4 serves as a central transcriptional regulator of cardiac metabolic function and mitochondrial dynamics, reactivating fetal cardiac genes during hypertrophic development (83, 84). In vivo studies have shown that KLF4 can modulate isoproterenol-induced cardiac hypertrophy by regulating myocardin (MYOCD) expression and activity, and cardiomyocyte-specific knockdown of KLF4 exacerbates hypertrophy (85). Oxytocin (OT), a hormone involved in cardiovascular homeostasis, mitigates cardiac hypertrophy by targeting the lncRNA GAS5/miR-375-3p/KLF4 axis to inhibit the PI3K/AKT pathway (186). Moreover, TIEG1 has been identified as a critical player in cardiac hypertrophy (87). The TGFb Inducible Early Gene-1 (TIEG1) is classified as a member of the KLF10 family and is involved in gene transcription regulation (42). Subramaniam et al. (88) studied male mice aged 4–16 months and found that TIEG1-/- mice exhibited cardiac hypertrophy compared to wild-type animals. This finding demonstrates that TIEG1, a gene transcription inducer or repressor, can inhibit cell proliferation and induce apoptosis by activating the TGF-β/Smad pathway. KLF15 is a pivotal regulator of cardiac metabolic homeostasis, primarily governing myocardial lipid flux. It plays a significant role in controlling the transcriptional network associated with cardiac metabolism (187). Notably, KLF15 exerts its regulatory effects by negatively modulating pro-hypertrophic and pro-fibrotic markers such as brain natriuretic peptide (BNP) and connective tissue growth factor (CTGF) through the p38-MAPK signaling pathway. This pathway has been identified as a crucial negative regulator of cardiac hypertrophy (90). Deletion or inhibition of KLF15 reduces the suppression of pro-hypertrophic factors and the stimulation of fibrotic signaling pathways, resulting in Left Ventricular Hypertrophy (LVH) development (58, 89).

Ischemic Cardiomyopathy (ICM), generally referred to as systolic left ventricular dysfunction in the context of obstructive CAD, is the leading cause of HF worldwide (188, 189). Ventricular dysfunction in CAD patients is usually caused by the irreversible loss of viable myocardium after Acute Myocardial Infarction (AMI) (189, 190). According to research, KLF5 regulates ceramide accumulation and lipid metabolism after Myocardial Infarction (MI) (91). Furthermore, KLF5 is involved in the aggravation of Ischemic Heart Failure (IHF), and induced KLF5 increases the expression of some regulatory factors [including Serine-Palmitoyl-Transferase-Long-Chain-Base-Subunit (SPTLC)1 and SPTLC2], and ceramide biosynthesis, leading to systolic dysfunction and eccentric remodeling, thereby decreasing ejection fraction and exacerbating IHF (91).

Following infarction, the remaining surviving segmental myocardium adapts to chronic perfusion insufficiency by reducing its energy requirements blocking myofibrillar protein expression, with the heart preferentially relying on glucose absorption rather than fatty acids for energy supply. This gene expression reprogramming via fluctuations in the cellular microenvironment is known as epigenetic reprogramming (191–193). It has been reported that KLF15 is an upstream regulator of metabolic gene expression, and that it is negatively regulated by EZH2 (an epigenetic regulator) in a SET structural domain-dependent manner for cardiac metabolism and structural reprogramming (92). Additionally, KLF15 suppresses gene expression and negatively regulates adverse cardiac remodeling and hypertrophy in ICM progression (72, 92, 96). Specifically, KLF15 antagonizes the expression of various genes actively involved in cardiac remodeling. Rogers and Otis studied the mechanism of resveratrol (an antioxidant) in ischemic heart treatment. They found that chronic myocardial ischemia significantly reduced KLF15 expression, which then increased the transcription of TGF-β1 and Nox4 mRNA, and that sustained TGF-β1/Nox4 signaling led to the production of large amounts of oxidants, which aggravated OS in diseased hearts, as well as myocardial fibrosis and hypertrophy (194). Haldar et al. (93) reported that the KLF15-p53-p300 pathway may also be a therapeutic target in CVD treatment. Specifically, they found that KLF15 activation inhibits the p300-mediated p53 acetylation. On the other hand, KLF15 deficiency causes p53 hyperacetylation in the aorta and heart (93–95). Mice lacking KLF15 develop aortopathy and cardiomyopathy in p53-dependent and p300 acetyltransferase-dependent manners.

Globally, the morbidity and mortality levels due to HF have been on the rise, making HF a major threat to human health. The etiology of HF is multifactorial, and studies have shown that uncorrected overweight and obesity may be independent risk factors for development of CVDs (195). Evidence from previous experimental, clinical, and epidemiological studies has pointed to the existence of a distinct disease entity known as “obesity cardiomyopathy”, which occurs independently of other CVD risk factors such as hyperlipidemia, hypertension, and diabetes mellitus (196). “Obesity cardiomyopathy” refers to metabolic and functional abnormalities of the heart caused by obesity alone (197, 198). In general, chronic obesity is strongly associated with myocardial remodeling, and its clinical features may range from LVH and myocardial fibrosis which eventually evolve to HF (199–201). Obesity also affects myocardial electrophysiology, which increases the prevalence of atrial fibrillation (202, 203).

Multiple studies have shown that berberine prevents heart disease, controls cardiac remodeling (204–207), and ameliorates KLF4-dependent obesity-related cardiac damage (97, 98). Ding et al. (99) treated high fat diet-induced obese mice with berberine and found that this drug ameliorated myocardial mitochondrial biogenesis and activity. However, KLF4 silencing reduced the mitochondrial mass, ATP production, oxygen consumption, and lipid metabolism, which were upregulated by berberine treatment. It also reversed berberine's structural benefits on cardiac anti-hypertrophic and fibrotic, anti-inflammatory, and antioxidant properties. In summary, these findings suggest that KLF4 indirectly mediates obesity-associated cardiac injury, controls myocardial remodeling, and confers protection on the heart.