DNA damage can result from a variety of environmental factors, including ultraviolet radiation, radioactive substances, chemicals (such as benzene and asbestos), and lifestyle choices (such as smoking and dietary habits) (1). These factors can alter DNA structure and function through distinct molecular mechanisms, ultimately leading to genetic mutations or chromosomal abnormalities. Ultraviolet radiation and radioactive substances can directly harm the DNA double helix, causing base pair mutations or double-strand breaks. Chemical substances can indirectly induce DNA damage by forming DNA adducts or triggering oxidative stress. Accumulated DNA damage can cause permanent genetic alterations and increase the risk of cancer (2).

In eukaryotic cells, the DNA damage response (DDR) is a complex regulatory system that evolved to maintain genetic integrity and prevent the accumulation of damaged DNA (3). This mechanism evolved in response to environmental stressors such as ultraviolet rays, radioactive radiation, chemicals, and free radicals to support life and ensure reproduction. Eukaryotic cells have developed efficient monitoring and repair mechanisms to ensure genome stability. The core goal of the DDR mechanism is to accurately identify DNA damage and promptly initiate the repair process (4). The process starts with the detection of DNA damage by a complex formed by recognition proteins such as RAD9, RAD1, and HUS1, which act as ‘sentinels’ to sense damage and activate downstream kinase pathways (5). ATM and ATR kinases are rapidly recruited to the damage site upon detection of DNA damage, transmitting repair signals by phosphorylating downstream effector molecules, such as CHK1, CHK2, p53, and BRCA1 (6, 7). This phosphorylation cascade triggers multiple signaling pathways, halting the cell cycle to allow time for DNA repair. Additionally, the DDR mechanism involves the regulation of chromatin structure (8). Following DNA damage, the chromatin environment is restructured to facilitate access for repair proteins to the damaged site. ATM and ATR can phosphorylate histone H2AX to mark damaged areas and recruit additional repair proteins to this site. SIRT1 plays a pivotal role throughout the DDR process.

SIRT1, a member of the sirtuin protein family, is located in the 7q31.3 region of human chromosomes. It is involved in various cellular physiological processes through its deacetylase activity, including chromatin remodeling, DNA repair, the regulation of gene expression, cell metabolism, and aging (9–11). Recent studies have demonstrated that SIRT1 plays diverse roles in tumorigenesis and cancer progression. For example, Jin et al. reported that increased SIRT1 expression was linked to poorer prognosis in breast cancer, whereas Zhang et al. reported a significant association between high SIRT1 expression and reduced survival in esophageal squamous cell carcinoma (12, 13). These findings highlight the complex role of SIRT1 as both an oncogene and a tumor suppressor, depending on the cancer context (14–17).

SIRT1 regulates gene transcription and maintains chromosomal stability by deacetylating histone and nonhistone substrates. It plays a crucial role in cell signaling pathways, particularly in response to DNA damage and oxidative stress (18). In the DNA damage response mechanism, SIRT1 influences cell cycle progression and the response to damage by deacetylating specific transcription factors and repairing proteins such as p53 (19). The activity and expression of SIRT1 are central to maintaining the cellular metabolic balance and responding to environmental stress (20). Loss of SIRT1 activity in animal models leads to metabolic disorders and accelerated aging, whereas excessive activation is linked to extended lifespan and antiaging effects (21). Therefore, SIRT1 is a key player in maintaining chromosomal stability and cellular function and is a significant target for research on aging and related diseases, such as cancer, neurodegenerative diseases, and metabolic disorders (22). Recent studies have demonstrated a strong correlation between abnormal SIRT1 expression and dysfunction and the development and prognosis of various malignant cancers (14, 15). For example, Wang et al. reported that elevated levels of SIRT1 in solid tumors, such as liver and lung cancers, were linked to poorer overall survival rates (16). Uzelac et al. revealed an inverse relationship between SIRT1 expression and overall survival, progression-free survival, TNM stage, and lymph node metastasis in breast cancer (17). Similarly, increased SIRT1 expression has been associated with an unfavorable prognosis in colorectal cancer, esophageal squamous cell carcinoma, and gastric cancer (13, 23, 24). While the role of SIRT1 in specific cancer types has been extensively researched, there is a lack of comprehensive studies on its involvement in pan-cancers. Therefore, investigating the mechanisms of SIRT1 in pan-cancer is crucial for advancing cancer treatments.

In this study, we conducted a comprehensive analysis via multiple databases, including TCGA, GTEx, TISIDB, cBioPortal, STRING, GSCALite, and CancerSEA, to explore the gene expression, prognosis, protein interactions, and associated signaling pathways of SIRT1 in pan-cancer. Furthermore, we explored the correlation between SIRT1 expression and immune cell infiltration across 33 different types of cancer. Finally, we validated SIRT1 expression in cancer cell lines through qRT–PCR and WB experiments. Our research highlights the crucial role of SIRT1 in pan-cancer studies and establishes a foundation for uncovering its potential involvement in cancer development and therapeutic strategies.

SIRT1 is an NAD+-dependent deacetylase involved in important processes such as cellular metabolism, DNA repair, and the stress response. Owing to its key role in regulating cellular function, energy balance, and aging, SIRT1 has attracted much attention in a variety of diseases, especially cancer. Through bioinformatics analysis, we comprehensively evaluated the function of SIRT1 in pan-cancer. First, we analyzed the mRNA and protein expression of SIRT1 in multiple human organs, tissues, and cell lines and compared its expression patterns in various cancers. We then evaluated the diagnostic and prognostic value of SIRT1 and explored its differential expression in different immune subtypes and tumor cell subtypes. Additionally, we identified the common mutation types and sites of SIRT1, constructed its PPI network, and analyzed its role in key cancer pathways. Finally, we validated the overexpression of SIRT1 in KIRC via qRT–PCR and Western blotting, confirming its potential as a therapeutic target. To our knowledge, this study is the first to comprehensively investigate the expression and biological function of SIRT1 from a pan-cancer perspective.

Through analysis of the HPA database, we found that SIRT1 is expressed at both the mRNA and protein levels in various organs and tissues, with notably higher expression in the adrenal gland, testes, ovaries, bone marrow, and lymph nodes. These results are consistent with those of previous studies, indicating that SIRT1 has a broad biological functional distribution in the immune system, endocrine system, and certain hematopoietic tissues (42). However, we observed significant differences in SIRT1 expression across different cancer types. For example, SIRT1 expression was significantly reduced in cancers such as ACC, BLCA, BRCA, CESC, and COAD (p < 0.05), whereas higher expression levels were observed in KIRC, LUAD, and STAD. These findings align with those of prior studies, suggesting that SIRT1 may play different biological roles in different tumor types (43, 44). In terms of diagnostic value, our study demonstrated that SIRT1 has high diagnostic sensitivity in various cancers, particularly in KICH and ESCC, where the AUC values were 0.923 and 0.902, respectively, indicating extremely high diagnostic efficacy. Other cancer types, such as BLCA, BRCA, LUSC, and PAAD, also exhibited strong diagnostic performance (AUC > 0.7). These results are consistent with the literature, further supporting the potential of SIRT1 as a diagnostic biomarker for cancer. For example, Desy et al. (4) reported that SIRT1 has excellent diagnostic efficacy in breast cancer, with an AUC value of 0.933, indicating that it has high diagnostic sensitivity (45). Therefore, SIRT1 not only serves as a potential therapeutic target but also as a valuable biomarker for early cancer diagnosis.

Our study used KM analysis to evaluate the prognostic value of SIRT1 in 33 types of cancer. In KIRC and LGG, patients with high SIRT1 expression had significantly better OS than those with low SIRT1 expression. These results suggest that SIRT1 may play a protective role in these two cancers. This finding is consistent with those of previous studies. Tian et al. reported that the expression level of SIRT1 in KIRC tissue was significantly greater than that in normal tissue and was associated with a good patient prognosis (15). Another study showed that SIRT1 can inhibit tumor progression by inhibiting the activity of HIF-1α and reducing the ability of KIRC cells to adapt to hypoxic environments (46). In gliomas, studies have shown that SIRT1 activators can induce tumor cell apoptosis, suggesting that SIRT1 may be a potential target for glioma treatment (47). Notably, however, SIRT1 had the opposite effect on STAD compared with KIRC and LGG. STAD patients with high SIRT1 expression had shorter DSS. These results suggest that SIRT1 may play different roles in different cancers. Studies have shown that SIRT1 can accelerate the progression of gastric cancer by deacetylating β-catenin and promoting the activation of the Wnt signaling pathway (48). Therefore, the specific mechanism by which SIRT1 affects the occurrence and development of gastric cancer still needs to be further explored. Future studies should focus on the interaction between SIRT1 and the Wnt signaling pathway, as well as its role in different tumor microenvironments. In addition, we also found that the expression level of SIRT1 was significantly correlated with the PFI of patients with KIRC, LGG, and GBM and that it had a protective effect on all three cancers. The results of a recent meta-analysis revealed that high expression of SIRT1 was an independent prognostic factor for prolonged overall survival in patients with malignant tumors (14). This finding is consistent with the results of this study, further suggesting that SIRT1 may be a potential biomarker for determining tumor prognosis. In summary, these findings reveal the important role of SIRT1 in the prognosis of multiple cancers, but its function in different cancers may differ.

SIRT1 expression is significantly different in different cancer molecular and immune subtypes. Specifically, our analysis revealed that SIRT1 was differentially expressed in immune subtypes of 16 cancer types, including BLCA, BRCA, GBM, HNSC, and KIRC. This difference in expression pattern suggests that SIRT1 may participate in tumor immune regulation through multiple mechanisms. For example, in the C1 (wound healing) immune subtype, the high expression of SIRT1 may be related to its ability to promote angiogenesis and tissue repair. Recent studies have confirmed that SIRT1 can promote angiogenesis via the deacetylation of HIF-1α and the regulation of VEGF expression, providing support for tumor growth and metastasis (49). In the C2 (IFN-γ dominant) subtype, SIRT1 may play a role by negatively regulating the IFN-γ-mediated inflammatory response. Studies have shown that mice lacking SIRT1 exhibit a stronger IFN-γ response and antitumor immune response (50). For the C3 (inflammatory) subtype, changes in SIRT1 expression may affect the production of inflammatory factors and the infiltration of immune cells. Mechanistic studies have shown that SIRT1 can inhibit the release of inflammatory mediators by deacetylating key transcription factors, such as the NLRP3 inflammasome and NF-κB (51). In the C4 (lymphocyte-depleted) subtype, changes in SIRT1 expression may be closely related to the regulation of T-cell function. Recent studies have shown that SIRT1 can affect the activation and effector function of T cells by epigenetically modifying immune checkpoint molecules such as PD-1 (52). In addition, the mechanism of action of SIRT1 in the C5 (immune-silent) and C6 (TGF-β-dominant) immune subtypes has attracted much attention. Some studies suggest that SIRT1 may participate in maintaining the immunosuppressive tumor microenvironment by regulating the differentiation and function of MDSCs (53). The interaction between SIRT1 and the TGF-β signaling pathway may affect the EMT process and tumor immune escape (54). In addition to its expression in immune subtypes, our analysis revealed that SIRT1 was significantly differentially expressed in molecular subtypes of multiple cancers, such as BRCA, COAD, and ESCA. These findings suggest that SIRT1 may be involved in regulating the activity of specific cancer-driving gene mutations or signaling pathways.

We analyzed mutations in the SIRT1 gene across cancers via the cBioPortal online database and found that SIRT1 mutations were most frequent in UCEC, BLCA, UCS, STAD, and CHOL. These findings differ from those of previous studies. For example, earlier research reported that SIRT1 mutations were more common in colorectal cancer and non-small cell lung cancer (55, 56). Several factors could contribute to these discrepancies. First, the sample sizes and types included in different studies may vary, leading to biased results. Second, with the advancement of sequencing technologies and the increase in sample sizes, new mutation patterns can be identified in larger datasets. Despite the widespread occurrence of SIRT1 mutations across various cancers, the mechanisms underlying its role in cancer initiation and progression may differ. In UCEC, SIRT1 mutations may promote tumor cell proliferation and invasion by affecting estrogen signaling pathways (57). In contrast, in STAD, SIRT1 mutations may be associated with Helicobacter pylori infection and inflammatory responses (58). These findings suggest that the biological function of SIRT1 mutations should be studied with consideration of the specificity of different cancer types. In particular, in different tumor microenvironments, SIRT1 mutations may exert their effects through distinct signaling pathways or molecular mechanisms. Furthermore, SIRT1 mutations may be correlated with the clinical features and prognosis of cancer. For example, in PAAD, SIRT1 mutations are negatively correlated with overall survival (59), whereas in BRCA, SIRT1 mutations are associated with increased tumor grade and lymph node metastasis (54). These results suggest that SIRT1 mutations may serve as potential prognostic biomarkers to guide the clinical management of cancer. However, this hypothesis still needs validation in larger clinical cohorts. Recent studies have indicated that SIRT1 mutations may lead to altered enzymatic activity, thereby affecting downstream gene expression and signaling pathways and playing a key role in tumorigenesis and progression (60). However, different types of SIRT1 mutations may have different impacts on its function, necessitating specific analysis of the relationship between mutation types and tumors. In summary, further investigations into the functional consequences of SIRT1 mutations will help elucidate their specific roles in the mechanisms of tumorigenesis.

Functional enrichment analysis of SIRT1 revealed that SIRT1 regulates cancer development by activating or inhibiting several known key pathways in cancer. These results suggest that SIRT1 may be involved in the occurrence and progression of tumors through multiple mechanisms. Wang et al. reported that inactivation of SIRT1 and AMPK in the SIRT1/AMPK pathway was associated with increased proliferation, migration, and invasion in renal cell carcinoma. The activation of SIRT1 can inhibit the malignant behavior of renal cell carcinoma cells by restoring the activity of AMPK and inducing cell apoptosis, thereby weakening the invasiveness and migration ability of tumor cells (61). In the SIRT1/p53 pathway, SIRT1 hinders p53 activity by deacetylating it and preventing apoptosis. Wang et al. demonstrated that SIRT1 inhibits the activity of p53 via deacetylation; downregulates the expression of miR-101; and increases the level of KPNA3, thereby promoting the proliferation, migration and invasion of colorectal cancer and enhancing the resistance of tumors to the chemotherapy drug 5-FU (62). Dasgupta et al. reported that the upregulation of SIRT1 in the SIRT1/NOX4 pathway activated the NOX4-mediated oxidative stress response, leading to muscle breakdown and adipose tissue consumption, thereby exacerbating the occurrence of cancer cachexia. Inhibition of the SIRT1-NOX4 signaling axis can significantly alleviate the symptoms of pancreatic cancer-related cachexia (63). Moreover, in breast cancer cells, SIRT1 and FOXO4 collaborate to prevent cell apoptosis and promote tumor cell survival (64).

Our analysis of the correlation between SIRT1 and immune cell infiltration in 33 cancer types yielded results that were consistent with those of previous studies. We found that SIRT1 was positively correlated with the infiltration of eosinophils, T helper cells, Tcm, Tem, Tgd, and Th2 cells in most tumors but negatively correlated with the majority of other immune cell types. These findings align with the known role of SIRT1 in regulating immune cell infiltration, particularly that of macrophages and T cells, as reported in earlier studies (65). In the context of cutaneous T-cell lymphoma (CTCL), our observation that SIRT1 inhibition induces cell growth arrest and apoptosis corroborates previous work highlighting its potential role in controlling immune cell proliferation and infiltration. These findings are further supported by studies demonstrating the involvement of SIRT1 in macrophage polarization toward the antitumor M1 phenotype via the NF-κB pathway and its ability to modulate B-cell activation through the PI3K/Akt/eNOS signaling axis (65, 66). Our findings on the impact of SIRT1 on Th2 immune responses through the regulation of transcription factors and metabolic pathways are consistent with prior research. For example, the inhibition of IL-9 production and subsequent prevention of Th9 cell differentiation by SIRT1 via histone deacetylation, as observed in our study, has been previously reported (67). Moreover, our results support the crucial role of mTOR-HIF1α axis-mediated glycolytic pathway activation in this differentiation process, confirming the dual role of SIRT1 in metabolic and transcriptional regulation, as suggested by earlier studies (60). The role of SIRT1 in maintaining memory T cells, particularly Tcm T cells, which we found to be positively correlated with SIRT1 expression, was previously attributed to its regulation of the PI3K/Akt/eNOS axis (66). Our observations of increased effector memory T-cell responses and reduced initial T-cell numbers under SIRT1-deficient conditions further emphasize its importance in immune memory formation, which is consistent with prior reports (68). With respect to γδ T cells, our findings on the regulatory function of SIRT1 through its influence on NF-κB, which enhances metabolic signaling for swift response capability, are in line with previous studies (69). The ability of SIRT1 to control inflammatory pathways and support glycolytic metabolism, as observed in our analysis, has been previously shown to enhance the function and proliferation of γδ T cells. In summary, our results confirming the ability of SIRT1 to regulate immune cell infiltration, Th2 immune responses, memory T-cell persistence, and γδ T-cell function are consistent with previous studies, reinforcing its key role in immune cell biology. The regulatory mechanisms involving transcriptional and metabolic pathways identified in our work have been supported by prior research, providing further insights into the potential of targeting SIRT1 for immune modulation in cancer and autoimmune diseases.

Finally, via qRT–PCR and WB experiments, we validated the upregulation of SIRT1 expression in KIRC, confirming previous findings. In summary, this study provides compelling evidence supporting the oncogenic role of SIRT1 across multiple cancers and highlights its promising potential as a therapeutic target for cancer treatment.

However, there are several limitations to this study. First, the sample sizes for certain tumor types in the database are relatively small, and variations in sequencing methods across different platforms and databases (e.g., TCGA, GTEx) may impact the accuracy and consistency of the data. These methodological differences, including variations in sequencing technologies and data normalization techniques, could affect the reliability and generalizability of the findings. Second, this study presents only preliminary evidence of the associations between SIRT1 and various cancers. Further experiments are needed to explore the specific molecular functions and mechanisms of SIRT1 in tumorigenesis, which will require the integration of multiomics data and the application of advanced experimental techniques. Additionally, the high heterogeneity of cancer may influence the effectiveness and specificity of SIRT1 as a diagnostic or prognostic biomarker, and the therapeutic efficacy of SIRT1-based interventions may vary among individual patients. Addressing these challenges will be crucial for translating the current findings into clinical practice. Nevertheless, this study provides a robust foundation for understanding the role of SIRT1 in cancer and offers valuable insights for the future development of precision-targeted therapies and immunotherapies.

This study systematically elucidates the role of SIRT1 in pan-cancer from multiple perspectives, including gene expression, prognosis, function, mutation sites, and immune cell infiltration. These findings reveal that SIRT1 expression is significantly downregulated in multiple cancers and displays differential expression across distinct molecular and immune subtypes. In most cancer types, increased SIRT1 expression is positively associated with eosinophils, helper T cells, central memory T cells, effector memory T cells, γδ T cells, and Th2 cells. Moreover, SIRT1 expression is strongly associated with immunoregulatory factors across different cancers. SIRT1 is capable of activating or inhibiting multiple cancer-related pathways and is intricately involved in immune infiltration and immune regulation. Our study provides a solid foundation for understanding the role of SIRT1 in cancer and provides valuable insights for the development of future precision targeted therapies and immunotherapies.