Atherosclerosis is a typical aging-related chronic CVD that poses a significant threat to human health and is one of the leading causes of death among the elderly (Kong et al., 2022). As individuals age, metabolic and immune functions decline, increasing the risk of atherosclerosis. Research has shown that TGR5 expression levels significantly decrease in aging mouse models, whereas TGR5 activation significantly improves aging-related cardiovascular dysfunction (Wang et al., 2017). In animal models, TGR5 activation has significantly reduced plasma total cholesterol and triglyceride levels, as well as atherosclerotic lesion areas in the aortic root, underscoring its crucial role in regulating lipid metabolism (Biagioli et al., 2023). Additionally, in macrophages, TGR5 activation downregulates the expression of scavenger receptor A (SR-A) and cluster of differentiation 36 (CD36), which are pivotal in the uptake of oxidized LDL (oxLDL) and foam cell formation (Xia et al., 2020). Consequently, TGR5 activation reduces the uptake of oxLDL by macrophages, inhibiting foam cell formation and mitigating the lipid deposition process in atherosclerosis. These suggest that TGR5 plays a pivotal role in regulating various physiological and pathophysiological processes, exhibiting remarkable protective effects against the development of atherosclerosis.

Given TGR5’s multifaceted protective roles in atherosclerosis, its potential as a therapeutic target is gaining increasing attention. Various TGR5 agonists have been developed and demonstrated promising anti-atherosclerotic effects in animal models. For instance, INT-777 significantly inhibits the development of atherosclerosis in mouse models, reducing macrophage content within plaques (Miyazaki-Anzai et al., 2018). Additionally, the application of nanotechnology has enhanced the bioavailability and targeting of TGR5 agonists, laying the groundwork for future clinical trials (Moretti et al., 2018). Figure 1 shows the role of TGR5 in atherosclerosis. However, therapeutic strategies targeting TGR5 still face significant challenges. For instance, systemic activation of TGR5 agonists may disrupt bile acid homeostasis, potentially inducing biliary dysfunction or gastrointestinal adverse effects (Fleishman and Kumar, 2024; Ye et al., 2024). Additionally, the extent of TGR5 signaling activation may vary due to individual genetic backgrounds (such as GPBAR1 polymorphisms) or differences in gut microbiota composition, leading to inconsistent therapeutic responses (Zhao et al., 2023; Pavlovic et al., 2017). The dose-dependent effects observed in preclinical studies also suggest that careful optimization of dosing regimens in human trials is necessary to avoid desensitization or receptor downregulation risks (Van Nierop et al., 2017).

MI is predominantly observed in the elders. However, dysregulation of immune pathways, impaired suppression of post-MI inflammation, spatially restricted inflammatory responses, and excessive fibrosis can lead to adverse cardiac remodeling, significantly impairing cardiac function. In recent years, the role of bile acids and their receptors in CVDs has garnered increasing attention. A study investigating changes in plasma bile acid levels in patients with acute MI found significantly reduced levels of DCA (Wang et al., 2021). This observation led researchers to investigate the role of DCA and its receptor TGR5 in the context of MI. In a mouse model of MI induced by ligation of the left anterior descending coronary artery, subsequent studies demonstrated that DCA binding to TGR5 significantly improved cardiac function and reduced ischemic injury (Wang et al., 2021). These findings highlight the protective role of DCA in MI and suggest that TGR5 could be a promising therapeutic target. Additionally, DCA was found to suppress the expression and activation of IL-1β, thereby mitigating inflammation-induced myocardial damage (Forteza et al., 2023).

To further explore the role of TGR5 in MI, researchers have conducted investigations into its impact on the immune system. In TGR5^−/− mice, the proportions of CD4⁺ T and CD8⁺ T cells in the heart and spleen remained elevated, with significantly increased CD4⁺ T cell infiltration in ischemic areas (Cheng et al., 2022). This suggests that TGR5 may regulate CD4⁺ T cell function post-MI. To test this hypothesis, researchers performed MI surgeries in CD4-specific TGR5-knockout mice. Compared to controls, these mice exhibited more severe ischemic injury, significantly reduced cardiac function, and larger infarct areas, further confirming TGR5’s critical role in post-MI cardiac repair and remodeling (Cheng et al., 2022).

At the cellular level, additional studies have shed light on TGR5’s mechanisms of action. In rat H9C2 cardiomyocytes and human cardiomyocytes subjected to ischemia/reperfusion injury, TGR5 expression was significantly upregulated (Li et al., 2020). This upregulation is likely an adaptive response to ischemic injury, aiming to mitigate damage through TGR5 activation. Further experiments revealed that TGR5 activation improved cell proliferation, reduced apoptosis, and decreased the mRNA and protein levels of inflammatory factors, suggesting that TGR5 confers cardioprotective effects by suppressing inflammation and enhancing cell survival (Li et al., 2020).

Notably, the pro-survival effects of TGR5 activation may entail metabolic trade-offs (Su et al., 2024; Guo et al., 2016). Enhanced cAMP signaling could exacerbate arrhythmogenic risks, particularly in aged hearts with preexisting calcium dysregulation (Grammatika Pavlidou et al., 2023; Lin et al., 2018). Interestingly, the protective effects of TGR5 were partially reversed when cells were treated with the AKT inhibitor MK-2206 (Li et al., 2020). This finding indicates that TGR5 may exert its protective functions through the AKT/GSK-3β signaling pathway. Given the pivotal role of the AKT/GSK-3β pathway in cell survival, proliferation, and apoptosis, TGR5 likely modulates this pathway to safeguard cardiomyocytes from ischemic injury. Additionally, the dual role of TGR5 in post-ischemic inflammation resolution and fibrotic repair remains incompletely understood, necessitating time-dependent modulation to avoid maladaptive remodeling (Wang et al., 2022; Kaya et al., 2019).

HF is a terminal stage of various CVDs, is characterized by diminished cardiac pump function. Recent studies have revealed a close relationship between TGR5 and aging-related HF. Changes in TGR5 expression and function in elderly HF patients may influence cardiac function and repair processes (Xu et al., 2024). MI is a major trigger for HF, as myocardial necrosis and scar formation after MI lead to structural and functional alterations in the heart, predisposing it to HF (Jiang et al., 2023). TGR5 likely plays a pivotal role in this transition by promoting myocardial repair and regeneration, reducing inflammation, and improving cardiac function, thereby preventing HF progression (Yan et al., 2024).

In the elderly population, cardiac hypertrophy is often pathological and closely related to cardiac dysfunction, significantly impacting their quality of life and overall health status (Tracy et al., 2020). Multiple studies have confirmed that the activation of TGR5 can inhibit the onset and progression of cardiac hypertrophy. In an H9C2 cardiac hypertrophy model induced by high glucose, LCA reduces the mRNA levels of hypertrophic markers such as calcineurin (CaN) and nuclear factor of activated T-cells (NFAT) in a dose-dependent manner (Cheng et al., 2019). Furthermore, upon activation of TGR5 by LCA, cAMP levels rise, subsequently activating PKA and increasing the phosphorylation of phospholamban (PLN) (Cheng et al., 2019). This process reverses the downregulation of SERCA2a expression, which is a crucial step in improving cardiac function. These findings suggest that TGR5 activation modulates intracellular calcium homeostasis and inhibits the CaN/NFAT signaling pathway, thereby reducing calcium ion accumulation in cardiomyocytes and promoting myocardial energy metabolism, ultimately inhibiting cardiomyocyte hypertrophy.

Additionally, in a myocardial hypertrophy model induced by endothelin-1 (ET-1), TGR5 activation significantly suppressed the increase in cardiomyocyte surface area and total protein, as well as the expression of hypertrophic markers such as atrial natriuretic peptide (ANF) and β-myosin heavy chain (β-MHC) (Chi et al., 2024; Jen et al., 2017; Wang et al., 2024). TGR5 activation may also protect cardiomyocytes from damage by inhibiting inflammation and oxidative stress, further inhibiting cardiac hypertrophy (Xu et al., 2024; Cheng et al., 2019).

In a DCM model, TGR5 plays a regulatory role in cardiac hypertrophy. Cardiac-specific TGR5^−/− mice exhibit more severe cardiac dysfunction and myocardial hypertrophy, while TGR5 activation can prevent lipotoxicity and cardiac dysfunction, inhibiting cardiac hypertrophy (Fleishman and Kumar, 2024; Wang et al., 2024). This may be related to TGR5’s inhibition of fatty acid uptake and the localization of CD36 in the plasma membrane, as CD36 is the main mediator of long-chain fatty acid uptake. By inhibiting CD36-mediated fatty acid uptake and lipotoxicity, the energy metabolism and inflammatory responses of cardiac cells are improved, thereby slowing or reversing the development of cardiac hypertrophy (Shu et al., 2022).

During the aging process, the risk of cardiac fibrosis significantly increases (Izzo et al., 2021). Cardiac fibrosis serves as a common pathological basis for various CVDs, including HF and MI, and is also a critical factor contributing to the gradual decline of cardiac function (Jiang et al., 2021).

Emerging evidence suggests that the activation of TGR5 may inhibit the onset and progression of cardiac fibrosis through multiple pathways. With advancing age, the body’s energy metabolism and lipid metabolism functions gradually decline, resulting in abnormal lipid deposition in tissues such as the heart (Xie et al., 2023). However, the activation of TGR5 can promote energy expenditure and lipid metabolism, reducing lipid accumulation in cardiac tissue and thereby effectively inhibiting the occurrence of cardiac fibrosis (Wang et al., 2024). The activation of TGR5, on the other hand, can protect cardiac tissue from injury by inhibiting inflammatory responses and oxidative stress pathways (Doroszko et al., 2020). In animal models, it has been observed that TGR5 activation reduces the expression of inflammatory factors and the generation of oxidative stress products in myocardial tissue, thereby inhibiting the progression of cardiac fibrosis (Xu et al., 2024; Yin et al., 2023). The activation of TGR5 may regulate the expression of genes related to extracellular matrix (ECM) synthesis and degradation, suppressing the activation and proliferation of cardiac fibroblasts, and thus reducing collagen fiber deposition (Yin et al., 2023). For example, by inhibiting the expression of fibrosis factors such as transforming growth factor-β (TGF-β), TGR5 can decrease the activation of cardiac fibroblasts and the synthesis of ECM (Reilly-O'Donnell et al., 2024; Sweeney et al., 2020). In a mouse model of myocardial fibrosis induced by a combination of isoproterenol and ursodeoxycholic acid (UDCA), research has found that UDCA, through the activation of TGR5, significantly alleviated the degree of myocardial fibrosis and reduced the expression of type I and III collagen, as well as TGF-β1 protein (Reilly-O'Donnell et al., 2024; Li et al., 2017). This finding further supports the potential role of TGR5 in cardiac fibrosis.

Hypertension, as a chronic disease that is widespread globally, has a significantly higher prevalence with age, posing a serious threat to public health (Mills et al., 2020). During the aging process, the activation of TGR5 stimulates energy expenditure and lipid metabolism, reducing the accumulation of lipids in vital tissues such as the heart and blood vessels, thereby lowering the risk of hypertension (Wang et al., 2023). Furthermore, TGR5 can inhibit the expression of the epithelial sodium channel (ENaC) in the kidney, decreasing sodium reabsorption and subsequently lowering blood pressure (Xu et al., 2025). This mechanism has been validated in mouse models treated with deoxycorticosterone acetate (DOCA), highlighting the significant role of TGR5 in renal sodium handling (Xu et al., 2025).

Beyond its direct effects on the kidney, TGR5 also participates in blood pressure regulation by influencing water and electrolyte balance. Studies have shown that TGR5 activation can modulate the expression and trafficking of AQP2 (aquaporin-2) in renal medullary collecting duct cells via the cAMP pathway, thereby affecting water reabsorption and urine concentration, and indirectly regulating blood pressure (Guo et al., 2024). Additionally, TGR5 activation induces the expression of eNOS and the production of NO, while promoting the generation of hydrogen sulfide and inhibiting endothelin signaling (Ma et al., 2021; Fiorucci et al., 2017). These effects collectively promote vasodilation and reduce blood pressure. Nevertheless, TGR5-mediated regulation of renal ENaC and AQP2 may be attenuated by age-related tubular dysfunction, contributing to interindividual variability in antihypertensive efficacy (Tamma et al., 2015; Tiwari et al., 2009). Moreover, central TGR5 activation, which suppresses sympathetic activity, may unpredictably interact with conventional therapies (such as β-blockers), warranting pharmacokinetic studies to elucidate synergistic or antagonistic mechanisms.

Notably, the activation of TGR5 can significantly ameliorate hypertension symptoms, which is associated with decreased levels of norepinephrine, improved myocardial cell morphology, and reduced inflammation and oxidative stress in the paraventricular nucleus (PVN) (Li et al., 2024). This finding suggests that TGR5 may serve as a central regulator of blood pressure, modulating sympathetic nerve activity and cardiovascular function.

Moreover, the gut microbiota plays a pivotal role in blood pressure regulation, and changes in its composition are closely linked to hypertension (Ge et al., 2024). TGR5 is closely related to gut microbiota function, as evidenced by the significant remodeling of the gut microbiota observed in TGR5^−/− mice (Zhan et al., 2024; Ma et al., 2020). This further confirms the role of TGR5 in gut microbiota regulation. Bile acids, as ligands of TGR5, not only activate TGR5 but also regulate the composition and function of the gut microbiota, forming a potential feedback loop for blood pressure regulation (Ishimwe et al., 2022). Table 1 briefly summarizes the role of TGR5 and aging-related CVDs.