Atherosclerosis, a prevalent and pathologically complex cardiovascular disorder, is characterized by the progressive accumulation of lipid deposits and fibroproliferative changes within the arterial wall, leading to luminal stenosis, vascular stiffening, and compromised hemodynamic function (Libby, 2021). This chronic inflammatory disease process involves the formation of atheromatous plaques, which are complex structures comprising lipid cores, vascular smooth muscle cells (VSMCs), and inflammatory infiltrates including macrophages and lymphocytes within the arterial intima (Certo et al., 2024). The pathophysiological progression of atherosclerosis typically initiates with endothelial dysfunction, followed by the development of fatty streaks that evolve into advanced plaques, ultimately resulting in significant luminal obstruction or complete vascular occlusion. The distribution of atherosclerotic lesions predominantly affects large and medium-sized arteries, with a particular predilection for coronary, cerebrovascular, and peripheral arterial systems. The course of atherosclerotic plaques involves progressive calcification and vascular remodeling, contributing to arterial rigidity and impaired vascular compliance. Of particular clinical significance is the phenomenon of plaque vulnerability, characterized by thin fibrous caps, large lipid cores, and intense inflammatory activity, which predisposes to plaque rupture and subsequent thromboembolic complications. In recent years, Tan IIA has emerged as a promising therapeutic agent in atherosclerosis management.

Primary hyperlipidemia, a condition with significant genetic underpinnings, arises from either monogenic or polygenic defects affecting key components of lipoprotein metabolism, including receptors, enzymes, and apolipoproteins (Tomlinson, 2025). A prominent example is familial hypercholesterolemia, which typically results from genetic mutations affecting cell surface lipoprotein receptors, lipoprotein lipase functionality, or structural components of lipoproteins and apolipoproteins. These genetic alterations lead to congenital lipid metabolism disorders, ultimately manifesting as hyperlipidemia (Maidman et al., 2024). The pathogenesis of primary hyperlipidemia often involves complex gene-environment interactions, although the precise mechanisms remain incompletely understood. Genetic polymorphisms can significantly influence lipid metabolism pathways, while environmental factors may modulate gene expression and metabolic processes. Dietary habits play an essential role in the progression of hyperlipidemia, with excessive consumption of high-fat foods and caloric intake leading to fat accumulation that surpasses the body’s metabolic capacity. Furthermore, high carbohydrate intake can stimulate insulin secretion and enhance hepatic synthesis of very low-density lipoprotein, predisposing individuals to hypertriglyceridemia. Obesity represents a significant risk factor for hyperlipidemia, as increased adipose tissue mass disrupts lipid homeostasis and elevates circulating lipid levels. This condition often coexists with other metabolic disorders, including diabetes mellitus and hypertension, which can further exacerbate lipid metabolism abnormalities. Additionally, various systemic diseases can induce secondary hyperlipidemia through multiple mechanisms. Conditions such as diabetes mellitus, hypothyroidism, non-alcoholic fatty liver disease, nephrotic syndrome, and gout can interfere with normal lipid metabolic processes, leading to dyslipidemia (Driessen et al., 2023; Liu X. et al., 2024).

Recent studies have elucidated the multifaceted mechanisms through which Tan IIA and its derivatives modulate lipid metabolism and alleviate hyperlipidemia. Jia et al. demonstrated that Tan IIA ameliorates hyperlipidemia in rat models by modulating hepatic lipid metabolism through regulation of key enzymes and receptors, including cytochrome P450 family 7 subfamily A polypeptide 1 (CYP7A1), LDLR, sterol regulatory element binding protein-2 (SREBP-2), and lecithin cholesterol acyltransferase (LCAT), additionally, Tan IIA influenced macrophage cholesterol efflux through regulation of ABCA1 and CD36 expression (Jia L. Q. et al., 2016). Further mechanistic insights revealed that Tan IIA reduces lipid deposition by suppressing miR-33a and modulating the SREBP-2/proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway (Jia L. et al., 2016). The therapeutic potential of STS has been demonstrated in various experimental models. Zhong et al. reported that STS protects against high-fat diet-induced hyperlipidemia by enhancing antioxidant capacity through activation of the Nrf2/HO-1 pathway (Zhong et al., 2020). Liu et al. further demonstrated that STS improves vascular dysfunction in hyperlipidemic mice by inhibiting spleen tyrosine kinase phosphorylation through modulation of the NLRP3 inflammasome-MMP2/9 pathway (Liu H. H. et al., 2024). At the cellular level, Tan IIA exhibits significant effects on lipid homeostasis and ER stress. Experimental evidence shows that Tan IIA reduces lipid accumulation by alleviating ER stress-induced unfolded protein response through activation of the peroxisome proliferator-activated receptor α (PPARα)/fibroblast growth factor 21 (FGF21) axis (Pi et al., 2024). In HepG2 cells, Tan IIA demonstrates protective effects against palmitate-induced lipid accumulation and apoptosis by suppressing ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), and C/EBP homologous protein (CHOP) (Wang et al., 2020d). Furthermore, Gao et al. reported that Tan IIA attenuates hepatic lipid accumulation by down-regulating lipogenic genes such as fatty acid synthase (FASN), acetyl-CoA carboxylase-1 (ACC1), and stearoyl-CoA desaturase-1 (SCD1) through modulation of the liver X receptor α (LXRα)/SREBP1 pathway (Gao et al., 2021). The interplay between inflammation and lipid metabolism represents another therapeutic target of Tan IIA. Huang et al. demonstrated that Tan IIA reduces plasma lipid levels by ameliorating oxidative stress and inflammation through PPARγ activation and TLR4 downregulation (Huang et al., 2019). Similarly, Li et al. found that STS inhibits lipogenesis and moderates fat accumulation by suppressing pro-inflammatory cytokines through activation of the SIRT1/AMP-activated protein kinase α 1 (PRKAα1) pathway (Li X. X. et al., 2019).

Hypertension represents a systemic vascular disorder rather than a localized vascular lesion, involving multiple organ systems including the cerebral, coronary, renal, and retinal circulations (Mandorfer et al., 2025). The pathogenesis of hypertension involves complex interactions between vascular structural changes and neurohormonal regulation. Progressive vasoconstriction and luminal narrowing of resistance vessels, characterized by arterial wall thickening and reduced elasticity, lead to increased peripheral vascular resistance and subsequent elevation of blood pressure (BP). Besides, alterations in central nervous system function and dysregulation of neurotransmitter systems, including norepinephrine, dopamine, and enkephalins, can induce sympathetic nervous system hyperactivity. This results in elevated plasma catecholamine concentrations, which potentiate vasoconstriction of resistance arterioles and contribute to sustained BP elevation (Kim and Thiruvengadam, 2024). Additionally, activation of the renin-angiotensin-aldosterone system (RAAS) in response to various stimuli plays a pivotal role in the development and progression of hypertension. Renal pathophysiology significantly contributes to hypertension through mechanisms involving sodium and water retention, increased cardiac output, and subsequent elevation of peripheral vascular resistance. Furthermore, various modifiable risk factors have been identified in the etiology of hypertension, including chronic tobacco use, excessive dietary sodium intake, obesity, sleep deprivation, and chronic psychological stress (Faraci and Scheer, 2024). These factors interact with genetic predispositions to influence vascular tone regulation, fluid homeostasis, and neuroendocrine function, ultimately contributing to the development of sustained hypertension.

Pharmacological modulation of calcium (Ca²⁺) and large-conductance calcium-activated potassium (BKCa) channels represents a crucial mechanism for regulating vascular tone under both physiological and pathological conditions. STS has demonstrated significant hypotensive effects in experimental models, primarily through its dual action on BKCa channel activation and Ca²⁺ channel inhibition. The vasorelaxant properties of STS are mediated through multiple mechanisms, including BKCa channel activation, retardation of Ca²⁺ channels, and inhibition of Ca²⁺ influx in VSMCs (Zhang X. D. et al., 2018). At the molecular level, Tan et al. demonstrated that STS activates BKCa channels by enhancing the membrane expression of the α subunit in both HEK293 cells and VSMCs (Tan et al., 2014). This BKCa-dependent vasodilatory effect has been specifically observed in the mesenteric arteries of spontaneously hypertensive rats (Zhou et al., 2019). Furthermore, Yang et al. confirmed that STS activates high-conductance Ca²⁺-activated K⁺ channels in porcine coronary artery smooth muscle cells, providing additional evidence for its potassium channel-mediated vasodilatory effects (Yang et al., 2008). The vasodilatory mechanisms of Tan IIA extend beyond ion channel modulation. Wang et al. revealed that Tan IIA enhances eNOS expression in HUVECs through the transient receptor potential vanilloid 4 (TRPV4)-NO-protein kinase G (PKG) signaling pathway (Wang P. et al., 2024). This finding is complemented by Fan et al.'s observation that Tan IIA’s vasodilatory effects are modulated through ER-dependent eNOS activation and calcium mobilization (Fan et al., 2011). Interestingly, STS exhibits unique vascular effects in pregnancy-related conditions, demonstrating effective dilation of uterine arteries and direct vasodilatory effects on vascular resistance arteries in pregnant rats through NO-independent mechanisms (Morton et al., 2015). Additionally, Yu et al. demonstrated that Tan IIA exerts antihypertensive effects and inhibits cerebrovascular cell proliferation in hypertensive rats by attenuating ET-1 expression through phosphoinositide-dependent kinase 1 (PDK1) inactivation (Yu et al., 2015).

MI primarily results from the obstruction of coronary blood supply, leading to myocardial hypoxia and ischemia. The predominant etiology of MI is coronary atherosclerosis, which causes narrowing or complete occlusion of coronary arteries. This obstruction impedes adequate supply of oxygenated blood and essential nutrients to myocardium, resulting in ischemic injury. Prolonged or severe ischemia can induce metabolic disturbances and cardiomyocyte damage, ultimately leading to cellular necrosis, which represents a core pathological feature of MI (Zhai et al., 2025). The progression of MI involves distinct pathological phases. During the ischemic phase, cardiomyocytes remain viable but sustain significant damage. In the subsequent necrotic phase, these cells undergo complete functional loss, releasing intracellular enzymes and organelles that trigger inflammatory responses and tissue remodeling. Histopathological examination reveals characteristic features of necrotic cardiomyocytes, including cellular swelling, organelle disintegration, and nuclear degeneration (Wei et al., 2025). A major therapeutic challenge in MI is ischemia/reperfusion (I/R) injury, wherein the reintroduction of oxygen-rich blood to hypoxic cardiac tissue paradoxically exacerbates cellular damage through mechanisms involving calcium overload, as excessive extracellular calcium influx leads to intracellular calcium accumulation and increased cardiomyocyte death (Ghanta et al., 2025). The pathophysiology of MI also involves complex inflammatory and oxidative processes. Tissue damage triggers cell membrane degradation and increased production of arachidonic acid metabolites, which recruit leukocytes to the injured site. These inflammatory cells adhere to vascular endothelium, further exacerbating endothelial injury. Concurrently, an imbalance between ROS production and antioxidant defenses initiates lipid peroxidation cascades. Oxygen free radicals impair ATP production, induce inflammatory mediator release, and cause membrane damage, collectively contributing to cellular death and myocardial injury progression.

Chen et al. demonstrated that STS attenuates endotoxin-induced cardiomyocyte pyroptosis and autophagy in mice through inhibiting NLRP3 inflammasome activation (Chen P. et al., 2021). This finding is complemented by Hu et al.'s research showing that STS ameliorates ischemia-induced myocardial inflammation in canine models by modulating NLRP3 inflammasome activation through restoration of PPAR-α expression via the JAK2-STAT3 pathway (Hu et al., 2015). The therapeutic potential of Tan IIA extends to its interaction with IGF-2R, a critical mediator in myocardial injury pathogenesis. Experimental evidence shows that Tan IIA inhibits Ang II-induced apoptosis in rat H9c2 cardiomyocytes and prevents subsequent cardiac remodeling by suppressing β-catenin nuclear translocation and IGF-2R inactivation (Chen et al., 2017). Weng et al. further demonstrated that Tan IIA protects H9c2 cardiomyocytes from injury through IGF-2R inhibition mediated by PI3K/Akt pathway activation (Weng et al., 2015). The antioxidative properties of STS contribute significantly to its cardioprotective effects. Yan et al. reported that STS reduces myocardial apoptosis in murine models by mitigating oxidative stress through modulation of the Keap1-Nrf2 pathway (Yan et al., 2018). These findings collectively highlight the multifaceted mechanisms through which STS and Tan IIA exert their protective effects against myocardial injury and infarction.

MI initiates a cascade of pathological cardiac remodeling that often progresses to HF. Zhang et al. demonstrated that STS attenuates post-MI pathological remodeling in mice through multiple mechanisms, including reduction of myocardial necrosis, suppression of inflammatory responses, and promotion of angiogenesis (Zhang B. et al., 2022). Chai et al. further elucidated that Tan IIA inhibits cardiomyocyte pyroptosis in a rat HF model following acute MI by down-regulating key inflammatory mediators IL-1β, pro-IL-1β, NLRP3, and caspase-1 through suppression of the TLR4/NF-κB p65 pathway (Chai et al., 2023). Additionally, STS has shown cardioprotective effects in isoproterenol-induced MI models by modulating fatty acid β-oxidation (Wei et al., 2013). The ER, crucial for protein synthesis and processing in cardiomyocytes, plays a significant role in MI pathophysiology. Under conditions of hypoxia, nutrient deprivation, or calcium imbalance, ER stress response is activated. Prolonged ER stress can lead to dysfunction and subsequent cardiomyocyte damage. Tan IIA has been shown to mitigate cardiomyocyte injury by alleviating ER stress through upregulation of SIRT1 expression (Wu S. et al., 2023). The tumor suppressor phosphatase and tensin homolog (PTEN) has emerged as a key regulator of cardiomyocyte apoptosis. Wang et al. reported that Tan IIA improves cardiac function in MI mice by promoting angiogenesis through modulation of miR-499-5p and PTEN expression (Wang and Wu, 2022). This finding is supported by Zhang et al.'s demonstration that Tan IIA inhibits apoptosis in rat H9c2 cardiomyocytes by up-regulating miR-152-3p and down-regulating PTEN (Zhang et al., 2016). Recent advances in understanding post-MI cardiac repair have highlighted the critical role of macrophage reprogramming. Modulation of macrophage metabolic pathways and functional phenotypes has shown potential in promoting cardiac repair and improving cardiac function (Hu et al., 2024; Xie et al., 2024). Gao et al. demonstrated that Tan IIA facilitates cardiac repair in post-MI mice by reprogramming macrophage phenotypes through inactivation of the phosphoglycerate kinase 1 (PGK1)/pyruvate dehydrogenase kinase 1 (PDHK1) pathway and remodeling macrophage energy metabolism (Gao et al., 2024).

While reperfusion therapy remains the gold standard treatment for myocardial ischemia, it inevitably induces myocardial I/R injury (Zhu et al., 2023). A systematic meta-analysis revealed that Tan IIA exhibits significant cardioprotective effects in rat models of I/R injury at doses exceeding 5 mg/kg, primarily via suppression of oxidative stress (Zhang X. et al., 2024). The protective mechanisms of Tan IIA and its derivatives against I/R injury involve multiple molecular pathways. Zhong et al. demonstrated that Tan IIA alleviates cardiac microvascular I/R injury by reducing mitochondrial apoptosis through activation of the SIRT1-PGC1α pathway (Zhong et al., 2019). This finding is complemented by Long et al.'s research showing that STS attenuates microvascular I/R injury through inhibition of fibrinogen-like protein 2 (FGL2) expression, fibrin deposition, and inflammatory responses via mediating Akt and NF-κB pathways (Long et al., 2015). Li et al. further reported that Tan IIA ameliorates myocardial I/R injury by suppressing NLRP3 inflammasome activation and regulating Th17/Treg cells differentiation (Li et al., 2022). The antioxidative and anti-inflammatory properties of STS contribute to its cardioprotective effects, as evidenced by its ability to enhance HO-1 activity and mitigate I/R injury (Wei et al., 2014). Fang et al. demonstrated that Tan IIA improves myocardial ischemia by reducing cardiomyocyte apoptosis and modulating apoptotic markers caspase-3, Cyto c, and Apaf-1 in myocardial tissue (Fang et al., 2021). Moreover, the ataxia-telangiectasia mutated (ATM) kinase, a crucial regulator of DNA damage response and genomic stability, has emerged as a potential therapeutic target in myocardial injury (Kukreja, 2014). Sang et al. showed that Tan IIA protects against I/R injury in H9c2 cardiomyocytes via ATM-mediated activation of the GADD45/ORC pathway (Sang et al., 2024). Besides, the composition of extracellular matrix changes significantly, collagen secretion decreases while hyaluronic acid accumulation increases competitively during acute MI, activated cardiac fibroblasts produce hyaluronic acid through hyaluronan synthase 2 (HAS2) (Little et al., 2025). Tan IIA has been shown to mitigate I/R injury in human AC16 cardiac cells by targeting the HAS2/fibroblast growth factor 9 (FGF9) axis, thereby reducing inflammation and oxidative stress (Wang Y. et al., 2024). Furthermore, Tan IIA protects against mitochondrial dysfunction through modulation of voltage-dependent anion channel 1 (VDAC1), an essential regulator of mitochondrial-cytoplasmic exchange. Hu et al. demonstrated that Tan IIA inhibits ferroptosis and apoptosis in H9c2 cardiomyocytes by down-regulating VDAC1 and preventing oxidative stress (Hu T. et al., 2023). The cardioprotective effects of Tan IIA extend to mitochondrial preservation. It protects H9c2 cardiomyocytes against anoxia/reoxygenation injury by inhibiting mPTP opening and apoptosis through upregulation of 14-3-3η, a protein that played a momentous protective role in cardiomyocytes (Zhang Z. et al., 2018). Wen et al. further demonstrated that Tan IIA alleviates I/R injury by regulating autophagy and maintaining mitochondrial function through 14-3-3η-mediated modulation of the Akt/Beclin1 pathway (Wen et al., 2023). Emerging therapeutic strategies utilizing mesenchymal stem cells (MSCs) have shown promise in CVDs treatment. Li et al. found that exosomes derived from Tan IIA-pretreated MSCs exert cardioprotective effects in myocardial I/R models by up-regulating miR-223-5p and inactivating CCR2, a protein-coding gene highly expressed in cardiomyocytes (Li S. et al., 2023).

Interestingly, Tan IIA demonstrates significant myocardial protective effects by modulating the crosstalk between the NLRP3 inflammasome and the Nrf2 antioxidant pathway, with its efficacy exhibiting a clear dose-dependent pattern. Mechanistically, Nrf2 activation is more responsive to oxidative stress, whereas NLRP3 inhibition requires higher Tan IIA concentrations to effectively suppress the inflammatory signaling cascade. At low doses, Tan IIA preferentially enhances antioxidant defenses, markedly up-regulating SOD activity and reducing MDA levels, while exerting only a modest inhibitory effect on NLRP3 inflammasome activation (Chen P. et al., 2021). In contrast, medium-dose Tan IIA achieves a balanced modulation of both pathways, simultaneously reducing myeloperoxidase (MPO) activity and IL-1β levels while significantly restoring ATP content, indicating coordinated anti-inflammatory and antioxidant actions (Vidal-Gomez et al., 2025). However, at high doses, Tan IIA may excessively suppress inflammatory responses, potentially compromising immune defense mechanisms (Wu S. et al., 2023). Collectively, Tan IIA mediates cardioprotection through a dynamic Nrf2-NLRP3 interaction network, exhibiting dose-dependent preferential effects: low-dose regimens favor anti-oxidative activity, high-dose treatments enhance anti-inflammatory efficacy, and intermediate doses promote synergistic regulation. These findings provide a mechanistic rationale for optimizing Tan IIA dosing in clinical applications. Future studies should further elucidate tissue-specific dose-response relationships and evaluate long-term safety profiles to facilitate translational development. A comprehensive summary of the myocardial protective effect of Tan IIA through crosstalk among NLRP3 inflammasome, NF-κB, and Nrf2 pathways is presented in Figure 3.

Cardiac hypertrophy, characterized by an increase in myocardial cells volume and consequent thickening of the ventricular wall, represents a complex adaptive response that can be either physiological or pathological in nature. Physiological hypertrophy, exemplified by the athlete’s heart, contrasts with pathological hypertrophy commonly observed in conditions such as hypertension and valvular heart disease. The pathogenesis of pathological myocardial hypertrophy primarily involves activation of neuroendocrine systems, particularly the RAAS and sympathetic nervous system, along with dysregulation of cellular signaling pathways including calcium ion channels and MAPK cascades (Chen et al., 2025). Myocardial fibrosis, characterized by excessive deposition of collagen and extracellular matrix components, represents another critical pathological process in cardiac remodeling. This fibrotic transformation, frequently associated with aging, obesity, and diabetes mellitus, significantly impairs cardiac function through multiple mechanisms. The accumulation of fibrous tissue increases myocardial stiffness, compromising ventricular diastolic function and impairing proper cardiac filling, ultimately reducing stroke volume and cardiac output (Skorka et al., 2025; Zhang et al., 2023). Furthermore, myocardial fibrosis disrupts the typical cellular architecture and electrophysiological properties of cardiac tissue, creating a substrate for arrhythmias that further compromise cardiac efficiency and contribute to the progression of HF (Lee et al., 2025). The excessive extracellular matrix deposition also physically restricts cardiomyocyte contractility, reducing myocardial contractile force and exacerbating cardiac dysfunction (Hosseinzadeh et al., 2024). The interplay between myocardial hypertrophy and fibrosis creates a vicious cycle in HF pathophysiology. Hypertrophic changes increase cardiac wall stress, promoting further cardiomyocyte enlargement and subsequent fibrotic transformation. The resulting fibrosis exacerbates myocardial stiffness and dysfunction, creating a self-perpetuating cycle of cardiac remodeling and functional deterioration. This complex interaction between structural and functional alterations underlies the progressive nature of HF development.

Tan IIA has demonstrated significant cardioprotective effects against cardiac hypertrophy and fibrosis through multiple molecular mechanisms. Experimental studies have revealed that Tan IIA attenuates cardiac hypertrophy in rat models by down-regulating collagen type I α-1 (COL1A1) mRNA expression through inhibition of the cystatin C (Cys-C)/Wnt pathway (Feng et al., 2017). Jiang et al. further elucidated Tan IIA’s potent anti-fibrotic properties, which are mediated through modulation of both TGF-β/Smad and MAPK/ERK pathways (Jiang et al., 2024). The therapeutic potential of Tan IIA extends to Ang II-induced cardiac fibrosis, where it enhances NO production and eNOS phosphorylation while inhibiting ERK phosphorylation (Chan et al., 2011). Zhang et al. demonstrated that Tan IIA alleviates acid-induced fibrosis by targeting the Nrf2-NLRP3 pathway, thereby reducing oxidative stress and inflammatory responses (Zhang W. et al., 2024). In the context of hypertension-induced cardiac remodeling, Tan IIA exhibits multifaceted protective effects. It mitigates left ventricular myocardial changes by reducing MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression, thereby improving cardiac function in renovascular hypertensive rats (Fang et al., 2010). Pang et al. reported that Tan IIA inhibits hypertension-induced left ventricular hypertrophy and fibrosis by modulating the TGF-β/Smads pathway while reducing MDA levels and enhancing SOD activity (Pang et al., 2014). Additionally, Jiang et al. found that Tan IIA suppresses cardiomyocyte hypertrophy and apoptosis in spontaneously hypertensive rats through regulation of Bcl-2, Bax, and p53 expression (Jiang et al., 2013). The antioxidative properties of Tan IIA contribute significantly to its cardioprotective effects. It improves cardiac function and reduces fibrosis in hypertensive models by decreasing NADPH oxidase activity, a major source of ROS in the heart (Wang et al., 2011). This mechanism is further supported by studies showing Tan IIA’s ability to inhibit H₂O₂-stimulated cardiac fibroblasts through suppression of collagen synthesis and NADPH oxidase activity (Wang et al., 2013). Tan IIA’s anti-hypertrophic effects are also mediated through inflammation modulation. It attenuates transverse aortic constriction-induced cardiac hypertrophy by reducing IL-6 and TNF-α levels, decreasing MDA content, and enhancing SOD activity via SIRT1 activation (Feng et al., 2016). Furthermore, Zhang et al. demonstrated that Tan IIA inhibits galectin-3 expression through modulation of N6-methyladenosine (m6A) methylation, thereby attenuating cardiac hypertrophy (Zhang M. et al., 2022). At the molecular level, Tan IIA influences microRNA regulation of cardiac remodeling. It inhibits hypertrophy and collagen deposition in rat heart tissues through upregulation of miR-618 (Yan et al., 2022). Mao et al. further reported that Tan IIA reduces collagen deposition in human cardiac fibroblasts by modulating MMP-2 and MMP-9 expression and regulating elastin deposition (Mao et al., 2014). The cardioprotective effects of Tan IIA extend to adrenergic stress-induced cardiac remodeling. It mitigates isoproterenol-induced cardiac hypertrophy by reducing brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and β-myosin heavy chain (β-MHC) levels through suppression of the calcineurin/NFATc3 pathway (Tan et al., 2011).

Emerging evidence has highlighted the crucial role of gut microbiota dysbiosis and gut-brain axis dysfunction in the pathogenesis of HF. Zhu et al. demonstrated that Tan IIA significantly attenuates myocardial apoptosis and fibrosis, subsequently improving cardiac hypertrophy and function in mice. This cardioprotective effect is mediated through inhibition of inflammatory responses and restoration of intestinal barrier integrity via modulation of the gut-brain axis (Zhu et al., 2024). The therapeutic potential of Tan IIA extends to chemotherapy-induced cardiotoxicity. Xu et al. reported that Tan IIA ameliorates doxorubicin-induced myocardial structural alterations and myofibrillar damage in HF mice through activation of the ERK1/2 signaling pathway (Xu et al., 2022). Wang et al. further elucidated that Tan IIA mitigates doxorubicin-induced HF by restoring autophagic flux through regulation of the Beclin1/lysosomal-associated membrane protein-1 (LAMP1) pathway (Wang et al., 2019). Innovative drug delivery systems have been developed to enhance Tan IIA’s therapeutic efficacy. Zhao et al. designed ROS-responsive triphenylphosphine-modified Tan IIA micelles, which demonstrated superior cardioprotective effects in doxorubicin-induced HF by reducing oxidative stress and inflammatory cytokine infiltration through mitochondrial activation in cardiomyocytes (Zhao et al., 2025). The molecular mechanisms underlying Tan IIA’s cardioprotective effects involve multiple signaling pathways. Experimental evidence shows that Tan IIA protects against HF by inhibiting myocardial apoptosis and promoting autophagy through activation of the AMPK-mTOR signaling cascade (Zhang et al., 2019). Chen et al. further demonstrated that Tan IIA attenuates cardiac dysfunction and fibrosis in HF models by reducing TGF-β, α-SMA, and MMP-9 expression in cardiac fibroblasts through suppression of oxidative stress (Chen R. et al., 2021). In the context of pressure overload-induced HF, Tan IIA exhibits significant therapeutic potential. Chronic pressure overload, characterized by increased resistance during cardiac contraction and relaxation, leads to pathological cardiomyocyte hypertrophy and subsequent cardiac insufficiency. Li et al. demonstrated that Tan IIA alleviates ventricular remodeling and improves cardiac function in HF mice via restraining inflammatory responses and cardiomyocyte apoptosis (Li X. et al., 2019).

Arrhythmia is defined as a disturbance in the frequency and/or rhythm of cardiac contractions resulting from abnormalities in the initiation and/or propagation of electrical impulses within the heart. The underlying mechanisms primarily involve irregularities in impulse formation and conduction, which can be influenced by various pathological factors, including pharmacological effects, drug toxicity, electrolyte imbalances, anesthesia, surgical interventions, cardiac catheterization, and autonomic nervous system dysfunction (Mondejar-Parreno et al., 2025). Arrhythmia arises when the electrical signals responsible for regulating cardiac contractions are delayed or obstructed. This disruption can occur due to either malfunctioning specialized cardiac pacemaker cells or impaired transmission of electrical impulses through the heart’s conduction system (Zeitler et al., 2024). Additionally, arrhythmia may result from ectopic electrical activity originating in other regions of the heart or abnormal propagation of impulses from pacemaker cells, both of which can interfere with the heart’s regular rhythmic activity. Furthermore, insufficient coronary blood flow can compromise the metabolic and functional integrity of cardiomyocytes, leading to alterations in myocardial electrophysiological properties and subsequent arrhythmogenesis (Yang et al., 2025). Electrolytes play a critical role in maintaining the regular electrophysiological activity of cardiomyocytes. Imbalances in the concentrations of key ions such as potassium, sodium, and calcium can significantly affect cardiomyocyte excitability, automaticity, and conductivity, thereby predisposing to arrhythmia.

He et al. demonstrated that Tan IIA effectively ameliorates atrial fibrillation in rabbits, with its anti-arrhythmic properties primarily attributed to the modulation of atrial electrophysiology. Specifically, Tan IIA prolongs atrial postrepolarization refractoriness (aPRR) and moderately increases interatrial conduction time (He et al., 2016). Shan et al. further elucidated that Tan IIA reduces the duration of arrhythmia and lowers the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) in rats. This effect is mediated through the upregulation of Kir2.1 expression by inhibiting miR-1, which expressed in the heart that regulates various ion channels and myocardial electrical activity under pathological conditions (Shan et al., 2009). Sun et al. identified Tan IIA as a potential activator of the human cardiac slow delayed-rectifier K⁺ current (I _Ks). Their findings revealed that Tan IIA activates human cardiac KCNQ1/KCNE1 potassium channels in HEK 293 cells by altering the channels’ kinetic properties (Sun et al., 2008). Despite these promising findings, research on the anti-arrhythmic effects of Tan IIA remains limited, and the precise pharmacological mechanisms warrant further investigation. A comprehensive summary of the effects and molecular targets regulated by Tan IIA in treating CVDs is presented in Figure 4 and Table 2. A comprehensive summary of Tan IIA’s efficacy against conventional cardiovascular drugs for CVDs is presented in Table 3.