Macrophages arise from early embryonic erythro-myeloid progenitors or from adult infiltrating monocytes. Upon antigen stimulation, macrophages are activated and polarized into pro-inflammatory or anti-inflammatory phenotypes, namely classical activation (M1) macrophages and alternative activation (M2) macrophages. M1 macrophages execute cytotoxic and tissue-damaging pro-inflammatory functions, while M2 macrophages play a crucial role in resolving inflammation and tissue repair (31). Within the SIRTs family, SIRT1, SIRT2, SIRT6, and SIRT7 participate in multiple specific stimuli and downstream signaling events of macrophage polarization, with significant implications for balancing macrophage polarization. Several studies have shown that deletion of the SIRT1, SIRT2, and SIRT6 genes in macrophages results in a significant increase in acetylation levels of the p65 subunit of NF-kB, leading to increased expression of NF-kB target genes IL-6, TNF-α, and IL-1β, inducing immune inflammation (32, 33). In other words, SIRT1, SIRT2, and SIRT6 inhibit inflammation in macrophages by deacetylating NF-kB (34). Rothgiesser et al. found that SIRT2 interacts with p65 in mouse embryonic fibroblasts, leading to deacetylation of p65 subunit of NF-kB at Lys 310, thereby increasing the expression of p65 acetylation-dependent target gene subsets, regulating the expression of specific NF-κB-dependent genes, and controlling a large number of target genes involved in immune and inflammatory responses, cell proliferation, differentiation, and apoptosis (35). Santos-Barriopedro et al. found that SIRT6 can bind to the histone methyltransferase Suv39h1 specific for H3K9me3 and induce monoubiquitination at the conserved cysteine residue in the PRE-SET domain of Suv39h1 (36). Upon activation of the NF-κB signaling pathway, SIRT6 upregulates the activity of the NF-κB inhibitor (IκBα) through cysteine monoubiquitination and chromatin eviction by Suv39h1, thus achieving inhibition of the NF-κB pathway and attenuating the aggravation of the immune-inflammatory response by SIRT6. In addition, the expression of SIRT7 decreases in an age-dependent manner in leukocytes of healthy individuals, and Phorbol-12-myristate-13-acetate(PMA)-mediated monocyte-to-macrophage differentiation in the monocytic THP-1 cell line increases SIRT7 expression, while SIRT7 overexpression also increases differentiation of non-stimulated THP-1 cells (37).

NK cells are cytotoxic lymphocytes that play a crucial role in innate immunity against viral infections and tumors. NK cells secrete perforins and granzymes, inducing apoptosis in target cells through the expression of cell death ligands on their surface. Additionally, NK cells secrete various pro-inflammatory cytokines, including TNF-α and interferon-beta (IFN-β), which play important roles in maintaining and amplifying immune responses through interactions with macrophages and dendritic cells (38). Studies have indicated a specific increase in the expression of SIRT2 in liver NK cells induced in mice with liver cancer, suggesting that SIRT2 promotes the activity of liver NK cells in response to hepatocellular carcinoma (HCC). Furthermore, overexpression of SIRT2 enhances the secretion of pro-inflammatory cytokines and cytotoxic granules by NK cells, thereby exhibiting increased anti-tumor activity (39). Additionally, SIRT2 activity is associated with increased phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2) and p38 mitogen-activated protein kinase (MAPK), which are two important signaling pathways for NK cell activity (40). Therefore, SIRT2 holds potential value in enhancing the anti-tumor effects mediated by liver NK cells.

Dendritic cells are antigen-presenting cells that, under steady-state conditions, exhibit high phagocytic activity and continuously present self-antigens to restrain T cell reactivity. Upon infection, dendritic cells mature, leading to an increased expression of co-stimulatory receptors, including CD80, CD86, and MHC-II molecules (41). When dendritic cells show weakened responses to pathogens but enhanced responses to self-antigens, it results in an increased expression of pro-inflammatory cytokines, leading to the breakdown of immune tolerance and inflammatory responses.

Research indicates that the expression of SIRT1 in dendritic cells increases when toll-like receptors (TLRs) are stimulated. Conversely, the absence of SIRT1 leads to changes in T cell polarization (42). In 2012, Alvarez et al. demonstrated that SIRT1 promotes the production of the signature cytokines IL-12 and TGF-β1 in a hypoxia-inducible factor α (HIF1α)-dependent manner, thereby regulating the differentiation of Th1 cells and Treg cells, participating in the process of immune tolerance regulation (43). Subsequently, Yang et al. found that in dendritic cells, SIRT1 interacts with interferon regulatory factor 1 (IRF1), a transcription factor associated with the expression of interleukin 27 (IL-27), and produces a deacetylation effect. This effect reduces the binding of IRF1 to the gene promoter of il-27p28, silencing it and decreasing the production of IL-27, promoting the differentiation of Th17 cells, which are a pro-inflammatory subset of T cells (44). In summary, SIRT1 is a major regulatory factor for cytokine production in dendritic cells and holds significant importance for the subsequent generation of T cell subsets. Apart from SIRT1, SIRT6 also participates in the differentiation and maturation of dendritic cells. Studies confirm that inhibiting SIRT6 significantly hinders the differentiation of monocytes into dendritic cells, resulting in immature dendritic cells with significantly reduced expression of CD86, CD80, and MHC-II molecules. Additionally, these dendritic cells exhibit increased phagocytic ability and a further decrease in the ability to stimulate lymphocyte proliferation (45, 46). At the same time, there is an increased proportion of cells producing TNF-α and IL-6, indicating that SIRT6 regulates the production of cytokines in these cells.

T lymphocytes comprise helper CD4+ T cells and cytotoxic CD8+ T cells, activated by TCR-specific antigens during cell-cell contact. Fagnoni et al. (47) propose an association between SIRT1 and the accumulation of CD8+CD28- T cells. Effros et al. (48) discovered that under conditions of CD28 co-stimulation deficiency, CD8+CD28- T cells exhibit heightened cytotoxicity, express pro-inflammatory cytokines, and display characteristics indicative of replicative senescence. During aging, SIRT1 undergoes autophagy-mediated degradation in various organs, including the spleen and thymus. Jeng and colleagues observed a notable decrease in SIRT1 levels in human CD8+ memory T cells, particularly CD8+CD28- T cells, without alterations in their gene expression. SIRT1, is a deacetylase for many transcription factors, including FOXO1, and regulates several cellular processes, such as proliferation, differentiation, and apoptosis. SIRT1 activation triggers apoptosis by directly inhibiting FOXO1 expression through deacetylation. Consequently, the loss of SIRT1 amplifies proteasomal degradation of its target FOXO1, thereby diminishing the cytotoxicity of memory T cells by enhancing their glycolytic capacity (49). Studies indicate a substantial decrease in SIRT2 levels in the spleens of aged rats, with an even more precipitous decline in SIRT2 levels in the thymus. Moreover, Sidler et al. (50) found that among the seven sirtuin genes encoded by the mammalian genome, only the expression level of SIRT2 decreases with age. This may be linked to the relationship between SIRT2 and Histone H4K16, a target of SIRT2 deacetylation in aging yeast (51). Reduced DNA methylation and H3K9me3 with age suggest the loss of heterochromatin as aging progresses. Additionally, SIRT6 plays a role in immune aging and inflammatory responses by regulating T cell inflammatory responses. A study of SIRT6 in aging demonstrated that targeted deletion of SIRT6 in T cells or the myeloid lineage recapitulated the inflammatory and fibrotic phenotype in the liver, suggesting autonomous regulation of inflammation by SIRT6 in immune cells (52). Importantly, SIRT1 levels are significantly upregulated in patients with GD, promoting the deacetylation of FOXP3 and mediating the simultaneous loss of IL-17+ T cells and Treg cells in Graves’ patients (53). Overexpression of SIRT1 in patients with IBD induces concurrent inhibition of Th17 cell differentiation and Treg cell differentiation, exacerbating colitis development. In conclusion, SIRTs actively participate in T cell differentiation processes, influencing immune responses and contributing to the occurrence of autoimmune diseases.

B lymphocytes constitute the cornerstone of adaptive immunity. Mature B cells predominantly reside in the spleen and lymph nodes, displaying antigen-specific immunoglobulins on their cell membranes. Upon infection, antigen-specific B cell clones are activated, leading to their differentiation into plasma cells that secrete antibodies or memory B cells.

The intrinsic relationship between SIRTs and B lymphocytes is currently under exploration. Nonetheless, it is established that SIRTs are linked to immunoglobulin class switch recombination (CSR), B cell homeostasis, and autoimmune suppression. Research indicates a significant role for SIRT7 in non-homologous end joining (NHEJ) repair. Regarding NHEJ, as one of the main DNA double-strand break repair modes in cells. NHEJ is different from homologous recombination in that it does not require homologous DNA as a repair template and can repair broken DNA at all stages of the cell cycle (54). In addition, NHEJ is involved in the recombination of diversified antibodies and T-cell receptors. Reduced expression of SIRT7 during aging may partly contribute to the diminished clonal diversity of newborn B cells, associated with immunosenescence (55). In a study by Gan in 2020, it was discovered that the activation of immunoglobulin CSR is mediated by activation-induced cytidine deaminase, and its expression in mature B cells is subject to epigenetic regulation. Enhanced activity of SIRT1 can lead to the deacetylation of H3K9Ac/H3K14Ac in the promoter of activation-induced cytidine deaminase, resulting in reduced expression and impaired CSR (56). Moreover, SIRT1 is crucial for B cell antigen presentation, as the loss of SIRT1 in B cells leads to decreased levels of MHC-II molecules expressed, thereby reducing their cross-presentation with CD4+ T cells (57). In summary, the downregulation of SIRT1 with age may compromise B cell immunity and contribute to immunosenescence.

Notably, during immunosenescence, inflammation and AID are commonly observed. In mature B cells of SLE patients, significantly lower levels of SIRT1 have been observed, and SIRT1 levels are negatively correlated with the frequency of CD19+ B cells in these patients (58). Activation of SIRT1 has a protective effect on RA patients, partly due to a reduction in the production of autoantibodies by B cells (59). Serum levels of SIRT1 in asthma patients are positively correlated with IgE levels (60), while anti-SIRT1 autoantibodies are more abundant in inflammatory diseases such as ankylosing spondylitis (61). In summary, SIRT1, by inhibiting the autoimmune response of B cells and reducing the cascade of immune inflammation, plays a crucial role in preventing severe invasion of various systems and organs in the body, maintaining the stability of the immune environment, and ensuring the normal functioning of the immune system.

RA is a systemic autoimmune disease characterized by erosive joint damage and systemic inflammation, affecting multiple systems (119). It is among the most prevalent systemic autoimmune diseases, with increasing prevalence and disability rates annually, particularly among middle-aged and elderly women aged 30–60, in regions such as North America, Europe, and Asia (120). The hazards of RA primarily involve joint damage and deformity, alongside systemic inflammation and elevated cardiovascular risk, significantly impacting patients’ quality of life and imposing a substantial global economic burden (121–123).

Oxidative stress is widely recognized as a major contributor to inflammation and arthritis. An increase in chemical reactions within the body, damage to antioxidant defense systems, and an imbalance between oxidants and antioxidants can lead to a sharp rise in ROS, culminating in the accumulation of reactive oxygen molecules and defects in DNA, RNA, and proteins (124). Studies have demonstrated that RES effectively scavenges radicals such as hydroxyl and superoxide, thereby inhibiting lipid peroxidation and DNA damage induced by excessive ROS production (125). Consequently, RES exhibits remarkable anti-inflammatory and antioxidant effects in RA. During oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor with antioxidant and anti-inflammatory properties, counteracts mitochondrial decay by interacting with antioxidant response elements (AREs) (126). Building upon this theoretical foundation, Li et al. revealed that RES can prevent calcium deposition and mitochondrial decay by activating the SIRT1/Nrf2 pathway, thereby inhibiting the phosphorylation and acetylation of NF-κB p65 and suppressing synovial hyperplasia and joint inflammation (127).

Given SIRT1’s capability to deacetylate various transcription factors, including NF-κB, it can modulate downstream cellular pathways associated with oxidative stress (128). Consequently, activating SIRT1-mediated NF-κB deacetylation to inhibit oxidative stress and inflammation has emerged as a potential therapeutic strategy for RA. In 2012, Rathore identified that NF-κB p65 directly targets the miR-29a-3p and miR-23a-3p promoters, downregulating the transcription levels of miR-29a-3p and miR-23a-3p, thus inducing immune inflammatory responses and oxidative stress in the body, leading to joint synovial damage (129, 130). Subsequently, Wang’s research in 2019 demonstrated that RES can inhibit the acetylation and phosphorylation of NF-κB p65, increase the transcriptional activity of miR-29a-3p and miR-23a-3p promoters, block fibroblast-like synoviocyte (FLS) proliferation, and mitigate oxidative stress induction mediated by miR-29a-3p and miR-23a-3p promoters, thereby alleviating ROS-induced damage to joints and surrounding tissues (131). In summary, RES regulates the activation of the SIRT1/NF-κB/miR-29a-3p/Keap1 pathway and the SIRT1/NF-κB/miR-23a-3p/cul3 pathway, subsequently activating the Nrf2-ARE signaling pathway, effectively inhibiting oxidative stress resulting from ROS accumulation and mitigating joint inflammation, positioning it as a promising candidate drug for RA prevention and treatment.

Thalhamer et al.’s research highlights the pivotal role of MAPK signaling pathways in RA, particularly emphasizing the significance of p38 MAPK (132, 133). Essentially, ROS trigger inflammation by activating the MAPK signaling pathway, which subsequently induces the production of pro-inflammatory cytokines, perpetuating a detrimental cycle of immune-driven inflammation resulting in severe bone erosion (134). In 2018, Yang et al. demonstrated that the functional inhibition of p38 MAPK by RES underpins its protective effects against RA progression (135). Specifically, RES can activate SIRT3, thereby restoring enzymatic activities of isocitrate dehydrogenase 2 (IDH2), superoxide dismutase 2 (SOD2), and glutathione peroxidase (GSH-Px) in endothelial cells, and promoting the deacetylation of SOD2 and forkhead box O3A (FoxO3A) (136, 137). Through this mechanism, RES diminishes ROS accumulation, inflammation, and angiogenesis in synovial tissue, inhibits p38 MAPK activation, and consequently exerts anti-inflammatory, anti-angiogenic, cell-inhibitory, and pro-apoptotic effects, exhibiting preventive potential against RA both in vitro and in vivo. Therefore, targeting p38 MAPK represents a promising approach for RA treatment, and RES emerges as a promising candidate for clinical RA therapy.

Khojah and colleagues conducted a randomized controlled clinical trial to investigate the efficacy of RES therapy in treating RA, wherein they found that RES effectively reduces the levels of TNF-α, IL-1β, IL-6, monocyte chemoattractant protein 1, and soluble receptor activator of NF-κB ligand in both serum and joint tissues (138). Subsequent studies indicate that RES achieves this reduction by upregulating SIRT1 expression levels, resulting in a significant decrease in NF-κB expression and thereby mitigating inflammation and bone degradation (139). Furthermore, RES demonstrates regulatory effects on inflammatory arthritis in rodents by selectively inhibiting cellular and humoral responses associated with RA development (59). Additionally, RES induces apoptosis in RA patients’ fibroblast-like synoviocytes (FLS) by activating caspase-8, leading to substantial apoptotic cell death through both mitochondrial signaling pathway convergence and caspase-dependent pathways (140). Consequently, the emergence of RES presents a promising, efficacious, and safe therapeutic option for RA treatment (141).

SLE patients produce autoantibodies such as antinuclear antibodies (ANA) that attack their own tissues and organs, releasing large amounts of inflammatory mediators such as TNF-α and IL-6, thereby triggering immune and inflammatory responses (142). SLE is a globally distributed systemic autoimmune disease involving genetic susceptibility genes and environmental factors such as infections, drugs, and ultraviolet light in its pathogenesis (143). Currently, SLE is widely recognized worldwide due to its complex clinical manifestations and severe complications. Its hazards mainly include lupus nephritis, cardiovascular diseases, central nervous system damage, risks of infection and bleeding, affecting female fertility, and increasing pregnancy risks. Severe cases may lead to systemic multi-organ damage and lupus crisis (144–148).

Research indicates a close relationship between CD4+ T cells and B cells in SLE (149). In humoral immunity, helper T cells interact with B lymphocytes, stimulating their proliferation and differentiation, leading to the production of autoantibodies against nuclear components, thereby attacking self-tissues and organs (150), ultimately triggering systemic autoimmune diseases. However, the SIRT1 activator, RES, inhibits activator protein-1 (AP-1) transcriptional activity by up-regulating SIRT1 expression levels, further inhibiting T cell activation and maintaining peripheral T cell tolerance (151). Simultaneously, RES can also induce the deacetylation of Fas, Bcl-2, Bax, and p53 by activating SIRT1 and SIRT3, and trigger Caspase 9-mediated cell apoptosis (152, 153). This mechanism achieves an inhibitory effect on CD4+ T cells and B cells, leading to a reduction in the production of anti-nuclear antibodies and the suppression of SLE immune inflammation-mediated damage to systemic tissues (154).

In 2010, Dorrie and colleagues discovered that antigen-presenting cells (APCs) present antigens to initial T cells to initiate immune responses during the recognition phase of the immune response, and some APCs present antigens to differentiated T cells during the effector phase to trigger antigen elimination. RES can influence the maturation of dendritic cells and their antigen-presenting ability in vitro (155). Additionally, RES can inhibit COX expression by suppressing NF-κB activation and inhibit TNF-α-induced inflammation response in fibroblasts by exciting SIRT1 (156), thereby reducing the deposition of immune complexes in the kidneys (157). Therefore, inflammation inhibition mediated by RES may also be beneficial in reducing the occurrence of lupus nephritis. In their investigation of lupus nephritis, Miyake et al. delineated the pivotal roles of Th1 and Th17 cells in the pathogenesis of diffuse proliferative lupus nephritis, while emphasizing the significance of Th2 cell cytokines in membranous lupus nephritis (158). Subsequently, Wang et al. utilized RES as a therapeutic intervention and elucidated its dose-dependent reduction in the Th1/Th2 cell ratio, thereby ameliorating the deleterious effects associated with diffuse proliferative lupus nephritis (159). Moreover, this study yielded a groundbreaking discovery, demonstrating that RES effectively mitigates proteinuria, diminishes IgG and IgM deposition in renal tissues, and attenuates renal histopathological lesions. These findings collectively suggest that RES holds promise in halting the progression of lupus nephritis.

Neuropsychiatric lupus erythematosus (NPSLE) is mainly characterized by brain vasculitis mediated by vascular endothelial growth factor (VEGF) (160). The polymorphism of genes encoding VEGF is closely related to the increased incidence of neuropsychiatric lupus (161). In 2018, Kalinowska-Lyszczarz et al. treated lupus-prone atherosclerotic mice with RES and found a significant decrease in VEGF expression, indicating that RES can reduce the occurrence of NPSLE inflammation, promote neuronal survival, and improve memory (162). The latest research indicates that any trends observed in RES-treated NPSLE mice are A2A receptor-dependent (163). Moreover, in microglia, RES counteracts the negative effects of A2A receptors by exciting SIRT1, reducing the expression of fractalkine (CX3CL1), inhibiting inflammatory responses, and improving cognitive function (164). In conclusion, the anti-inflammatory properties of RES can exert strong protective effects in NPSLE.

SSc is a chronic autoimmune connective tissue disease characterized by fibrosis and vascular abnormalities of the skin and internal organs. The disease usually severely affects the skin, oesophagus, lungs, heart, kidneys, and other organ systems, and manifests itself in a diverse range of clinical symptoms and modes of disease progression (165).The onset of SSc is geographically and ethnically diverse. The incidence of SSc is notably higher in regions such as Europe, North America, and Australia, while relatively low rates are observed in Asia, Africa, and Latin America. Additionally, the prevalence of SSc is lower among individuals of African descent and Asians, whereas those of European descent and Indian Americans exhibit higher rates. Typically, SSc affects individuals in the young to middle-aged demographic, spanning ages 20 to 50. Factors contributing to its onset include infections, occupational exposures, substance use, and lifestyle choices (166). The risks associated with SSc are multifaceted. Firstly, there’s the potential for damage to both the skin and internal organs. SSc induces fibrosis and dysfunction in these areas, where skin sclerosis can significantly impact appearance and quality of life, while organ involvement may result in compromised function, such as pulmonary fibrosis, cardiac issues, and renal impairment. Secondly, vascular complications are common. SSc often presents with both microangiopathy and macrovascular lesions, potentially leading to symptoms like Raynaud’s phenomenon and hypertension. Thirdly, there’s immune system dysregulation to consider. SSc is characterized by autoimmune processes, wherein aberrant immune activation can spur the production of autoantibodies and inflammatory cytokines, precipitating tissue inflammation and damage. Lastly, joint and muscle involvement can occur, manifesting as arthritis, joint swelling, and muscle weakness, which can significantly hinder daily activities and motor function (167).

Research suggests that the decline in SIRTs levels and activity contributes to the pathogenesis of SSc (168). Conversely, activating SIRTs can induce anti-fibrotic effects, offering therapeutic benefits for SSc patients. Specifically, when SIRT1 is activated, it inhibits the TGF-b/SMAD signaling pathway, reducing collagen release by fibroblasts and blocking tissue fibrosis (169). Notably, Zhu and colleagues discovered that RES inhibits inflammatory factor expression by activating the SIRT1/mTOR signaling pathway. By downregulating mTOR, it diminishes collagen levels, alleviating skin inflammation and fibrosis in SSc (170). Additionally, RES enhances SIRT3 expression, increases intracellular TGF-b deacetylation, hinders intracellular TGF-b signaling and fibrotic responses, and mitigates the activated phenotype of fibroblasts in SSc (171). This leads to a substantial reduction in mitochondrial and cytoplasmic ROS accumulation in fibroblasts, lessening oxidative stress damage (172). In conclusion, RES improves fibrosis by activating SIRT1 and SIRT3, thereby inhibiting TGF-b-induced signal transduction. Moreover, RES activates SIRT1 to obstruct the mTOR pathway, restraining collagen fiber accumulation. Consequently, RES emerges as a potential pharmaceutical intervention for treating SSc.

GD arises from the immune system erroneously attacking thyroid tissue, leading to hyperactivity of the thyroid gland and excessive secretion of thyroid hormones, causing an elevated metabolic rate. Approximately one-third of patients may also develop eye conditions, such as protruding eyes and eyelid swelling, known as Graves’ ophthalmopathy (GO) (173). GD, a prevalent autoimmune disease globally, predominantly affects women aged 20–40, with genetics and environmental factors closely linked to its onset. Particularly, environmental factors such as smoking, excessive iodine intake, and ionizing radiation play significant roles (174). Hazards associated with GD encompass thyroid dysfunction, thyroid storm, eye complications, an increased risk of cardiovascular diseases, and osteoporosis (175–178).

Kim et al. illustrated that RES inhibits adipogenesis in orbital fibroblasts associated with GO (179). Acting as a broad-spectrum SIRTs activator, RES diminishes the rate of ROS generation triggered by oxidative stress and lowers heme oxygenase-1 (HO-1) levels through the activation of SIRT1/3. This concurrent reduction extends to superoxide dismutase Cu/Zn-SOD (SOD1), catalase, and thioredoxin (Trx), thereby reducing adipocyte numbers and lipid droplet accumulation. Furthermore, RES induces adipocyte apoptosis within fibroblasts (180, 181). Consequently, RES holds promise in mitigating orbital lipid deposition, ameliorating ocular complications of GO, and emerging as a significant therapeutic modality for managing GD and its ocular sequelae. Nonetheless, the research in this domain remains limited, necessitating further investigation into RES’s therapeutic effects on GO via the SIRT1 signaling-dependent pathway.

T1DM is a chronic metabolic disorder characterized by insufficient or complete lack of insulin production, leading to elevated blood sugar levels. This disease is typically caused by autoimmune destruction of pancreatic β-cells, rendering insulin unable to be effectively secreted (182). T1DM is more common in children, adolescents, or young adults and is associated with factors such as family history, viral infections, early-life environment, and dietary factors. It is worth noting that T1DM is associated with other autoimmune diseases (such as RA, autoimmune thyroid diseases, etc.), suggesting the presence of common genetic or immune factors (183). Its hazards mainly include several aspects: Firstly, cardiovascular diseases. Hyperglycemia increases the risk of cardiovascular diseases, including myocardial infarction, stroke, atherosclerosis, etc., which are among the main causes of death in diabetic patients (184). Secondly, retinal lesions. High blood sugar damages retinal blood vessels, leading to retinal lesions and potential blindness (185). Thirdly, renal damage. High blood sugar harms the kidneys, leading to diabetic nephropathy, which may require dialysis or kidney transplantation in severe cases (186). Fourthly, neuropathy. Hyperglycemia damages the nervous system, causing peripheral neuropathy (such as sensory abnormalities, pain) and autonomic neuropathy (such as gastrointestinal dysfunction, cardiovascular dysfunction) (187). Fifthly, foot complications. Neuropathy and vascular changes increase the risk of foot infections and ulcers, potentially leading to amputation (188).

In 2015, Côté et al.’s study showed that compared with saline, RES significantly increased the levels of NAD+ and its ratio to NADH in the duodenal mucosa (189). Subsequently, by detecting the acetylation level of liver kinase B1 (Lkb1) in cells after RES treatment, it was further confirmed that RES significantly increased SIRT1 activity (190–192). Specifically, RES activates AMPK, thereby activating SIRT1 to achieve its biological effects (192). The activation of the Glp1r-Pka dependent signaling in the duodenum is downstream of the metformin-AMPK sensory pathway (193), so the duodenum naturally becomes a site of action for RES. Therefore, RES reduces hepatic glucose production (HGP) by activating the duodenal AMPK-Sirt1→Glp1r-Pka dependent neural pathway, exerting a hypoglycemic effect similar to metformin (194). This not only lays the foundation for the development of intestine-specific targeted therapy but also collaboratively reduces HGP and blood sugar in diabetic and obese patients, becoming a new targeted treatment for diabetes.

RES is not only one of the new therapeutic drugs for lowering blood sugar but also has broad prospects in the prevention and treatment of diabetes-related complications. In 2016, Park et al. showed that RES can increase the expression of adiponectin receptors 1/2 (AdipoR 1/2) and activate the AMPK-SIRT1-PGC-1α axis, thereby alleviating endothelial dysfunction caused by lipotoxicity, oxidative stress, and apoptosis, and preventing diabetic nephropathy (195, 196). At the same time, RES can also prevent diabetes-induced nephritis and mesangial cell proliferation by inhibiting the Akt/NFκB pathway (197). Subsequent studies have found that RES reduces ROS production and lowers blood sugar by activating the AMPK pathway and inhibiting the expression of NADPH oxidase 4 (NOX 4) in renal tubular epithelial cells (198). In summary, RES reduces renal fibrosis and restores renal function by regulating the AMPK/SIRT1/NOX 4/ROS signaling pathway (199), achieving prevention and control of diabetic nephropathy, and reducing the immune-inflammatory damage of the kidneys caused by diabetes.

Negi et al. found that long-term high blood sugar levels can cause oxidative stress in the body, leading to the activation of the transcription factor NF-κB in peripheral neurons (200). However, NF-κB can mediate the release of a large number of pro-inflammatory cytokines such as iNOS, TNF-α, IL-6, and COX-2, thereby driving nerve damage mediated by neuroinflammation and causing peripheral neuropathy (201). In 2020, Huang et al. found that RES can reduce the inflammatory mediators in diabetic neuropathy (202). Specifically, RES upregulates the expression of SIRT1 and downregulates the expression of NF-κB, thereby reducing the activity of pro-inflammatory factors (such as TNF-α, IL-6, and iNOS) associated with neurodegeneration (203). Furthermore, RES can also ameliorate sensory motor disturbances associated with diabetic neuropathy by inhibiting the activity of TNF-α and nicotinamide adenine dinucleotide phosphate oxidase through activating SIRT1 (204, 205). Therefore, RES reduces the release of pro-inflammatory factors in diabetic patients, prevents oxidative stress from attacking neuronal cells, protects nerve function, and alleviates neuropathy.

In vitro studies have shown that RES reduces the expression of VEGF in human retinal endothelial cells and inhibits high glucose-induced cell proliferation (206). It can also inhibit the migration of retinal endothelial cells by activating the PI3K/Akt pathway mediated by matrix-derived factors (207). Therefore, RES has potential value in preventing diabetic retinal lesions.

IBD is a group of chronic intestinal disorders, mainly including Crohn’s disease (CD) and ulcerative colitis (UC). The hallmark of these diseases is chronic inflammation of the intestinal mucosa, often accompanied by ulcer formation (208). The incidence of IBD varies in different regions, with higher rates in North America, Europe, and Australia, and relatively lower rates in Asia, Africa, and Latin America. IBD is more common in adolescents and young adults aged 20–40 and is associated with genetic factors, lifestyle, dietary habits, and infections. Particularly, smoking is closely associated with an increased risk of IBD (209). Its hazards mainly include intestinal inflammation and ulcers, malnutrition, intestinal obstruction, intestinal fistulas, and an increased risk of colorectal cancer (210–212).

Many in vitro and animal studies have shown that RES can reduce the severity of intestinal inflammation in IBD. However, the beneficial effects of RES on treating IBD are attributed to multiple mechanisms, which ultimately lead to the inhibition of the inflammatory cascade response (213). Ren et al. demonstrated that RES primarily exerts its inhibitory effect on NF-κB by activating SIRT1, thus mitigating the severity of IBD (214). Specifically, RES suppresses the transcriptional activity of p65 and the ubiquitination of NF-κB essential modulator (NEMO) in a dose-dependent approach, thereby inhibiting NF-κB activation mediated by the NF-κB kinase. Singh et al. found that RES not only downregulates TH1 responses to reduce the secretion of inflammatory factors such as IL-1β, IL-6, and TNF-α in colitic mice but also reduces the percentage of CXCR3+ T cells. More importantly, RES significantly induces the expression of immunosuppressive CD11b+ Gr-1+ myeloid-derived suppressor cells (MDSCs) in the colon, which helps suppress local effector T cell responses (215). Furthermore, RES markedly diminishes the populations of inflammatory CD4+ and CD8+ T cells, B cells, NK cells, and myeloid-derived suppressor cells (MDSCs), underscoring its efficacy in reversing the advancement of chronic colitis (216).

In a 2012 study on UC, it was proposed that IL-17, IL-10, and transforming growth factor β1 (TGF-β1) participate in the development of TH17 through two important pathways: mTOR-HIF-1β-TH17 and IL-6-STAT3-HIF-1β-TH17. RES precisely regulates the balance between Treg and TH17 cells by activating the SIRT1/mTOR/HIF-1β/TH17 signaling pathway, leading to cell cycle arrest in intestinal smooth muscle cells, increased apoptosis, and decreased collagen synthesis (217). Subsequently, in a study on CD, RES effectively reduced the expression of insulin-like growth factor 1 (IGF-1) and procollagen mRNA by activating SIRT1, thereby significantly decreasing the activity of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the fibrosis-promoting factor (TGF-β1) (218). This study elucidated that RES not only mitigates the inflammatory response but also impedes the fibrotic process of the cecal wall.

Furthermore, Arslan et al. found that RES can enhance the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) in vivo (219). The study report by Serra showed that RES is more effective than 5-aminosalicylic acid and can activate two pathways, nuclear factor erythroid 2-related factor 2 (Nrf2) (220), and PPAR-γ in human intestinal cells (221, 222). It is worth noting that these two pathways are currently considered as new therapeutic targets for IBD.

In summary, RES can inhibit ROS in the intestines and increase the activity of antioxidant enzymes through multiple pathways, thereby suppressing oxidative stress to maintain the balance between oxidants and antioxidants in the body, to some extent reducing the activity of IBD and improving the quality of life of patients with IBD.

PF is a chronic progressive lung disease and a component of connective tissue disorders. Its hallmark is the excessive proliferation and deposition of fibrous tissue in the lung tissue, leading to irreversible lung damage. This fibrosis can damage the alveoli and lung interstitium, making the lungs stiff and losing elasticity, thereby affecting respiratory function (223). PF has a relatively low incidence but is increasing annually, occurring more frequently in adult males over 60 years of age, and is associated with prolonged exposure to harmful chemicals (such as silica dust, asbestos, silicates, etc.) and inhalation of toxic gases (such as nitrogen oxides, iron oxide dust, etc.) (224). Its hazards mainly include the following aspects: firstly, impaired respiratory function. PF leads to excessive fibrous tissue proliferation in the alveoli and lung interstitium, thereby affecting lung function. Impaired lung function can cause symptoms such as dyspnea, shortness of breath, and in severe cases, may even require respiratory assistance from a ventilator, severely affecting the patient’s quality of life (225). Secondly, cardiovascular complications. PF can lead to the occurrence of cardiovascular complications such as pulmonary arterial hypertension and right heart failure, which can be life-threatening in severe cases (226). Thirdly, increased risk of cancer. Long-term chronic inflammation and tissue damage in the lungs may increase the risk of developing lung cancer (227).

In 2016, Li et al. discovered that the SIRT1 agonist RES reduces systemic oxidative stress by activating the Nrf2-related antioxidant defense mechanism, thus exerting a protective effect on PF (228). Importantly, Nrf2 can induce various downstream signaling targets, including NAD(P)H quinone dehydrogenase 1 (HO-1/NQO1), NADPH oxidase 4 (NOX4), and GSH. These signaling targets participate in the formation of multiple signaling pathways, such as the SIRT1-Nrf2-HO-1 pathway, thereby achieving anti-fibrotic effects both in vivo and in vitro through mechanisms such as inhibiting immune-inflammatory responses and oxidative stress, which significantly attenuates PF (229).The latest research indicates that RES can alleviate PF by inhibiting TGF-β-activated kinase 1 (TAK1) (230). TAK1 is a kinase involved in TGF-β activation, participating in fibroblast proliferation, collagen deposition, and scar formation (231). Zhang et al. demonstrated that moderate concentrations of RES can activate SIRT1, leading to enhanced expression of AMPK, reducing the activity of inflammatory cytokines such as IL-1β and macrophage inflammatory protein-1α (mip-1α), thereby preventing nitric oxide (NO) release, inhibiting iNOS expression, and suppressing NF-κB nuclear translocation (232). In studies on human alveolar epithelial cells (AEC2), RES upregulates the expression of SIRT1, thereby improving mitochondrial membrane potential, reducing ROS levels, decreasing cell apoptosis, ultimately reducing high oxygen-induced cell damage (233). Additionally, the activation of the SIRT1/p53 signaling pathway by RES can also delay the aging of AEC2 and participate in the treatment process of PF through its antioxidant and anti-inflammatory responses (234). Therefore, the SIRT1 and Nrf2 pathways induced by RES are likely to become potential therapeutic targets for PF.

Bolton et al. found that the metabolites of RES have cytoprotective effects but can also induce cytotoxicity or immunotoxicity (254). During the metabolism of RES, cytochrome P450 generates quinone compounds through hydroxylation reactions, producing the metabolite piceatannol. Piceatannol possesses anti-inflammatory and antioxidant properties. It not only enhances the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in human breast epithelial cells by inducing Nrf2 (255), but also inhibits the downregulation of the anti-apoptotic B-cell lymphoma 2 protein (Bcl-2), thereby suppressing oxidative stress and apoptosis induced by hydrogen peroxide and peroxynitrite (256). The quinone metabolites of RES are also associated with toxic effects, involving oxidative stress and alkylation mechanisms (257). For example, piceatannol can induce the inhibition of P450 oxidase or alkylation of certain proteins such as Keap1, Nrf2, I kappa B kinase (IKK), where NF-κB can lead to severe hepatorenal toxicity (258). Moreover, quinone compounds can deplete GSH, affect the function of nicotinamide adenine dinucleotide phosphate oxidase (NOX), and ultimately lead to oxidative stress reactions, damaging normal organisms (254). Studies have shown that tyrosinase, a key enzyme involved in melanin biosynthesis, participates in RES metabolism. RES can serve as a substrate for tyrosinase, generating active quinone compounds (259). The generated quinone compounds can decay to form oligomers, which as pro-oxidants, can trigger cytotoxicity in melanocytes, ultimately leading to the development of skin tumors (260).

Research has shown that increasing intake of RES can better clear ROS, thus, RES has a cellular protective effect (259). However, under certain conditions, antioxidants may also act as pro-oxidants, leading to accelerated lipid peroxidation or induced DNA damage (261). In fact, whether RES exhibits pro-oxidant or antioxidant activity depends on RES concentration, form, processing conditions, and its redox status (262, 263). When acting as a pro-oxidant molecule in vitro, RES can cause DNA damage, reduce multiple DNA repair pathways, and activate cytotoxicity and apoptosis pathways (264). Zuo et al. found that RES exhibits preferential cytotoxicity in malignant tumor cells, leading to higher electron transfer between RES and copper ions (265). Therefore, RES and copper-induced DNA damage may be one of the cytotoxic mechanisms of RES against cancer cells (266). It is noteworthy that the pro-oxidative action of RES has pro-apoptotic function in different types of cancer cells, and its ability to induce DNA breaks has potential therapeutic value in combating cancer cells (267). However, there are also reports that RES triggers p53-dependent apoptosis by activating topoisomerase II, thereby inducing DNA damage in colon cancer cells (268). In U2OS and A549 cancer cells treated with RES, the proportion of DNA double-strand breaks significantly increased. This phenomenon may also be mediated by RES-induced pro-oxidative effects and regulation of the CXCR2-p53 pathway (269).

Giordo et al. found that RES severely impacts cellular redox state (270). In this regard, low doses of RES have various beneficial effects, such as protecting cells and tissues from the effects of neurodegeneration, cardiovascular diseases, cancer, diabetes, and obesity-related diseases, and prolonging organism lifespan (271). However, there is substantial evidence indicating that RES exhibits a biphasic concentration-dependent effect. That is, both in vivo and in vitro, RES acts as an antioxidant at low doses and a pro-oxidant at high doses (272). The pro-oxidative effect of RES is typically associated with the downregulation of phosphorylated pkb/Akt, cell damage, and apoptosis. Meanwhile, ROS-mediated mitochondrial damage produced by cytochrome P450 enzyme cyp2c9 in high doses of RES-induced oxidative damage seems to be involved as well (273). Heo et al. proposed that RES can induce apoptosis and cell cycle arrest in malignant melanoma cells (274). Additionally, Kim found that RES induces caspase-dependent cell death in ovarian cancer cells through a ROS-dependent mechanism. It is worth mentioning that in their 2022 study, Elbaz et al. found that resveratrol also triggers the downregulation of miR-144 by upregulating the expression level of Nrf2.Consequently, resveratrol showed hepatorenal antioxidant, anti-inflammatory, and antiapoptotic activities as manifested by improvement in the antioxidant markers along with a decline in NF-κB, TNF-α, and caspase-3 expressions. In summary, this study demonstrated that resveratrol has potential therapeutic effects in alleviating liver and kidney damage induced by nonsteroidal anti-inflammatory drugs (275).

Currently, an increasing number of studies have found indirect interactions between RES and other drugs, leading to decreased activity or overexpression of major cellular systems involved in drug metabolism—drug transporters and CYP450 enzyme activity (276). Previous studies have shown that RES can blunt the function and expression of drug transporters, thereby increasing the anti-proliferative activity of various drugs and reducing their bioavailability (277). For example, RES inhibits drug transport proteins such as P-glycoprotein, multidrug resistance-associated protein 2 (MRP2), and organic anion transport proteins (OAT1/OAT3), reducing the clearance of methotrexate in the kidneys and increasing the risk of liver toxicity (278, 279). Additionally, RES can enhance the anticoagulant activity of warfarin, increasing the risk of bleeding (280). Interestingly, combination therapy with RES has also been reported to attenuate the effects of other drugs. For instance, RES can diminish the effects of human immunodeficiency virus (HIV) protease inhibitors (281) and interact with inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) (282), immunosuppressants (283), antiarrhythmic drugs (284), antihistamines (285), and calcium channel agonists (286), thereby reducing the bioactivity and utilization of drugs and affecting drug efficacy.