Search Results (7,159)

Background: Metabolic and alcohol-associated liver disease (MetALD) has been associated with an increased risk of cancer. However, it remains unclear whether combinations of favorable, intermediate, and adverse lifestyle behaviors differentiate cancer risk within MetALD. Methods: We analyzed 25,712 participants with MetALD using UK Biobank. Smoking, moderate-to-vigorous physical activity (MVPA), and diet were classified into favorable, intermediate, and adverse categories. Favorable and adverse behavior counts ranged from 0 to 3, and a unified lifestyle profile was constructed. Cox proportional hazards models were used to analyze adjusted hazard ratios (aHRs) and 95% confidence interval (CI) for incidence of all cancers. Results: During 296,965 person-years of follow-up, 4416 incident cancers occurred. Compared with no favorable behaviors, those having two favorable behaviors showed significance 0.92 (95% CI, 0.84–1.00). Compared with no adverse behaviors, the aHRs were 1.06 (95% CI, 1.00–1.13), 1.15 (95% CI, 1.04–1.27), and 1.11 (95% CI, 0.84–1.47) for one, two, and three adverse behaviors, respectively (p for trend = 0.003). The mixed/intermediate profile was associated with higher cancer risk than the favorable profile (aHR, 1.09; 95% CI, 1.02–1.16), whereas the adverse-profile estimate was not statistically significant. Among individual lifestyle behaviors, current smoking was associated with a higher cancer risk than never smoking (aHR, 1.20; 95% CI, 1.09–1.32; p < 0.001). Conclusions: Among participants with MetALD, favorable and adverse behavior counts showed opposite adjusted trends in cancer risk. Current smoking showed the strongest association with cancer risk among the individual behaviors. Full article

Background: Colorectal neoplasia in adults younger than 50 years has attracted increasing clinical attention because of the rising incidence of early-onset colorectal cancer. However, the clinicopathological characteristics of colorectal lesions detected in younger adults remain incompletely described. This study aimed to characterize the clinical, anatomical, and histopathological features of colorectal neoplasia in adults younger than 50 years undergoing colonoscopy. Methods: This retrospective single-center study included adults aged 18–49 years who underwent complete colonoscopy between January 2018 and December 2023. After exclusion of individuals with normal colonoscopy findings, 152 patients with at least one colorectal lesion were included. Lesions were classified as benign, advanced, or malignant according to established histopathological criteria. Demographic, endoscopic, and pathological characteristics were analyzed and compared across lesion categories. Results: Among 152 patients, 83 (54.6%) had benign lesions, 64 (42.1%) had advanced neoplasia, and 5 (3.3%) had malignant lesions. Advanced lesions were observed predominantly in individuals aged 40–49 years. Most lesions were detected in symptomatic patients undergoing clinically indicated colonoscopy. Histopathological evaluation demonstrated a higher frequency of villous/tubulovillous adenomas, sessile serrated lesions, and high-grade dysplasia among advanced lesions. Larger lesion size was strongly associated with advanced pathological features (p < 0.001). In multivariable analysis, patients aged 30–39 years had significantly lower odds of advanced or malignant neoplasia than those aged 40–49 years, whereas no independent associations were observed for sex, smoking status, alcohol use, family history of colorectal cancer, or lesion location. Conclusions: In this selected cohort of adults younger than 50 years with detected colorectal lesions undergoing clinically indicated colonoscopy, advanced neoplasia represented a substantial proportion of cases. These findings should not be extrapolated to the general population of adults younger than 50 years or to screening cohorts. Full article

Background/Objectives: Metformin is a prominent candidate for cancer drug repurposing, backed by preclinical and epidemiological evidence showing reduced cancer incidence in diabetic patients. Its pleiotropic effects include AMPK activation, protein synthesis inhibition, and metabolic alterations. This review integrates global preclinical data via a comprehensive tabular overview alongside a cross-analysis of specific investigations of hamster fibrosarcoma. Since head-to-head comparisons of metformin-based combinations on hamster fibrosarcoma remain limited, this work performs an integrated cross-study evaluation to establish a clear comparative hierarchy of various repurposed adjuvants combined with metformin. Methods: A literature review and cross-study re-analysis of peer-reviewed preclinical studies were conducted, focusing on in vivo therapeutic outcomes within the BHK-21/C13-induced hamster fibrosarcoma model. Treatment regimens from distinct primary studies were evaluated side-by-side using tumor endpoint data expressed as a percentage of control mean (± SD). Only statistically significant pairwise differences (p < 0.05) determined the comparative hierarchy. Results: Integrated analysis identified disulfiram and diclofenac as the most promising adjuvants among compared metformin combinations, showing the highest statistical significance across all evaluated endpoints. The statistical ranking of the metformin-based combinations followed a descending order: disulfiram, diclofenac, nitroglycerin, itraconazole, and caffeine. Conclusions: By synthesizing previously fragmented primary data into a unified comparative framework, these findings provide a strong, consolidated preclinical rationale for metformin-based combination strategies. The established hierarchy of adjuvant potency resolves structural ambiguity and supports further translational and clinical investigation to evaluate their therapeutic potential in fibrosarcoma and other malignancies. Full article

Background: Based on the demonstrated survival benefits of gemcitabine plus cisplatin (GemCis) therapy in the TOPAZ-1 and KEYNOTE-966 trials, GemCis plus immune checkpoint inhibitor (ICI) therapy has become a standard first-line treatment for unresectable biliary tract cancer. However, its safety and efficacy in elderly patients and those requiring biliary drainage remain insufficiently evaluated in real-world practice. We aimed to evaluate the efficacy and safety of GemCis plus ICI therapy, with a focus on elderly patients and those requiring biliary drainage. Methods: We retrospectively analyzed the clinical characteristics of patients with unresectable biliary tract cancer treated with GemCis plus ICI at our institution between April 2022 and September 2025. Progression-free survival (PFS) was analyzed using the Kaplan–Meier method, and prognostic factors were examined using Cox proportional hazards models. PFS and immune-related adverse events (irAEs) were compared between durvalumab and pembrolizumab. Results: Of the 51 patients diagnosed with unresectable biliary tract cancer during the observation period, 26 (51.0%) received GemCis plus ICI therapy. The median age was 73 years (range, 46–83 years), and 15 (57.7%) patients were male. Distant metastases were present in 22 patients (84.6%), and biliary drainage was performed in 15 (57.7%). The primary tumor sites were intrahepatic cholangiocarcinoma (n = 8), perihilar cholangiocarcinoma (n = 6), gallbladder cancer (n = 11), and cancer of unknown primary origin (n = 1). The ICIs used were durvalumab in 18 patients and pembrolizumab in eight patients. The median follow-up period was 214 days (range, 30–1114). The response rate was 28.6%, the disease control rate was 90.5%, and the transition rate to ICI maintenance therapy was 29.2%. IrAEs occurred in six patients (23.1%), with a significantly higher frequency in the pembrolizumab group than in the durvalumab group (50.0% vs. 11.1%). The median PFS was 8.2 months in the durvalumab group and 8.9 months in the pembrolizumab group, with no significant difference (p = 0.88). Multivariate analysis incorporating age, performance status, metastatic burden, and liver function confirmed that age ≥ 75 years remained the only independent predictor of shorter PFS (HR 5.62; 95% CI, 1.35–23.4; p = 0.02), whereas ICI regimen and biliary drainage were not significant prognostic factors. Conclusions: In clinical practice, GemCis plus ICI therapy showed no statistically significant difference in efficacy between ICI regimens in this small cohort, although this comparison was not statistically powered. Given the exploratory nature of these findings, the lower incidence of immune-related adverse events (irAEs) observed in the durvalumab group should be interpreted with caution. Age ≥ 75 years was associated with shorter PFS. Careful patient selection is warranted when considering GemCis plus ICI therapy in elderly patients with biliary tract cancer. Full article

Lung cancer mortality is a critical issue in Northern Thailand, where incidence rates significantly exceed the national average. Key risk factors include tobacco smoking and seasonal air pollution from biomass burning, which releases carcinogenic polycyclic aromatic hydrocarbons (PAHs). This study aims to analyze the accumulation of 16 priority PAHs in human lung tissues to explore links between environmental exposure, smoking habits, and cancer development. Tissue samples (normal, para-cancerous, and adenocarcinoma) were collected from 30 surgical participants (15 lung cancer patients, 15 non-cancer controls) at Chiang Mai University Hospital. Compounds were extracted via ultrasonication and quantified using gas chromatography-mass spectrometry. Carcinogenic potency was evaluated using Benzo[a]pyrene equivalents, with concentrations compared across tissue types and patient groups using generalized estimating equations. High-molecular-weight PAHs were the dominant species, accounting for over 50% of total accumulation in all tissues, aligning with regional biomass burning profiles. Total concentrations and carcinogenic potency were significantly higher in smokers, particularly within normal lung tissues. Furthermore, high-molecular-weight PAH concentrations positively correlated with tissue cholesterol levels (R = 0.66). Source analysis indicated exposure primarily from pyrogenic sources, alongside petroleum emissions. In conclusion, high-molecular-weight carcinogens significantly accumulate in human lungs in Northern Thailand, reflecting substantial environmental exposure, while tissue lipid content modulates toxin bioaccumulation. Smoking facilitates compound retention in normal tissues, underscoring an urgent need for targeted public health strategies addressing both environmental pollution and tobacco use. Full article

Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression. Full article

Background/Objectives: Skin cancer is a major health concern worldwide and has led to the quest for safer and more effective topical chemopreventive agents. In this study, the in vivo efficacy of a hydrogel formulation containing kaempferol and ferulic acid-loaded nanoparticles was evaluated for the management of DMBA-croton oil-induced skin cancer in Swiss albino mice. Methods: Drug-loaded nanoparticles prepared via nanoprecipitation were incorporated into hyaluronic acid to obtain single-drug (FAPG, KMPG) and dual-drug-loaded (FKMG) hydrogel formulations. Skin tumors were induced via DMBA as an initiator followed by croton oil as a promoter, with tumor onset observed after a similar latency period of approximately 5–6 weeks in all carcinogen-exposed groups. Treatment was initiated after week 6 and continued until week 16. Results: The gel formulation had a skin-compatible pH and the desired rheological and spreadability properties. The dual drug-loaded hydrogel formulation had a more controlled and prolonged release profile. Compared with the negative and vehicle control groups, the FKMG-treated group presented a marked reduction in tumor incidence and tumor burden, along with improved body weight gain. Biochemical analysis revealed the restoration of antioxidant and enzyme activity in treated animals, particularly in animals treated with FKMG. Histopathological examination revealed near-normal skin architecture in FKMG-treated mice, indicating strong protective effects. Additionally, significant downregulation of TNF-α and IL-6 suggested effective suppression of tumor-promoting inflammatory pathways. Conclusions: Overall, the FKMG formulation exhibited superior chemopreventive efficacy compared with the FAPG and KMPG treatments, highlighting its potential as a promising topical therapeutic strategy against chemically induced skin carcinogenesis. Full article

The African esophageal squamous cell carcinoma (ESCC) corridor extends from Ethiopia to the Eastern Cape and contains some of the highest age-standardized ESCC incidence rates reported anywhere, with five-year survival below 5%. The corridor’s heterogeneous incidence (sex ratios from 1:1 to 7:1; tenfold variation between adjacent populations) has resisted single-factor explanation through more than half a century of investigation. We synthesize the multicenter evidence accumulated since the IARC 2018 Group 2A classification of very hot beverages (>65 °C), with particular attention to the African Esophageal Cancer Consortium (ESCCAPE) outputs and to whole-genome sequencing. We argue, on the convergent evidence of animal toxicology, human in vitro mucosa, and population genomics, that thermal exposure acts as a tumor promoter rather than an initiator. On this reading, the corridor’s heterogeneous burden reflects heterogeneous chemical co-exposure profiles operating against a shared thermal-promoter substrate. Extending the comparative margin-of-exposure (MOE) methodology to esophageal squamous carcinogenesis, we present an MOE framework distinguishing genotoxic compounds (within-mode-of-action additive) from thermal exposure (separate companion figure) and apply it to two corridor scenarios. The framework supports a four-lever prevention strategy combining tobacco control, alcoholic-strength reduction in unrecorded spirits, clean-cookstove deployment, and graduated thermal-exposure reduction. Full article

Background: Mesothelioma is a rare but highly aggressive malignancy strongly associated with asbestos exposure. Owing to its long latency and poor prognosis, its burden requires systematic evaluation. Methods: Data on prevalence, incidence, deaths, disability-adjusted life years (DALYs), and age-standardized rates were extracted from the Global Burden of Disease Study 2023. The estimated annual percentage change, Joinpoint regression, Das Gupta decomposition, and Nordpred forecasting were used to assess temporal trends, identify turning points, quantify demographic and epidemiological contributions, and project future burden through 2045. Results: From 1990 to 2023, the absolute burden of mesothelioma in China increased substantially. Prevalent cases rose by 189%, incident cases by 150%, DALYs by 98%, and deaths by 142%. Males consistently showed a higher burden than females, and the burden was concentrated mainly among middle-aged and older adults. The age-standardized prevalence rate and age-standardized incidence rate increased, whereas the age-standardized DALY rate and age-standardized mortality rate remained stable or declined slightly. Decomposition analysis indicated that population growth and aging were the principal drivers of increased DALYs and deaths, while epidemiological change contributed negatively. Projections suggested that deaths may continue to increase through 2045, despite declining age-standardized fatal burden. Conclusions: This is the first update of the burden of mesothelioma in China over the past thirty-four years. The absolute burden of mesothelioma in China, as estimated by the GBD study, increased markedly, largely driven by demographic changes. Strengthening asbestos exposure surveillance, diagnostic standardization, and cancer registration systems would enable burden estimates to be derived from directly observed and certified data rather than relying primarily on model-based assumptions, while potentially identifying previously unrecognized sources of asbestos exposure. Full article

Clinical biochemical reports should reflect the clinical perspective, be well organized and biologically oriented, and present accurate reference values based on clinically relevant distributions. To illustrate possible quality issues, we selected Clinical Cases from The New England Journal of Medicine as it publishes comprehensive reports to teach internationally relevant high-level workups. We evaluated their organization with a system organ grouping and the consistency of reference values between comparable cases. We found that the ordering of tests varied across issues, and associated interpretative tests were not organized in a scholarly manner. In several cases, the reference values for hemoglobin did not align with WHO recommendations, the upper reference value for glycohemoglobin did not correspond to established guidelines, and the upper reference value for creatinine did not reflect internationally standardized methods. The ferritin reference values in young women were not adjusted for the postmenopausal age group. When searching for incident blood loss using a common reference in young women and those of postmenopausal age in a large primary health care cohort, the frequency of flagged low ferritin results was so low that the ratio of flagged results to the incidence rate of colorectal cancer was only 1.1 (0.95 confidence interval 1.0 to 1.3). In men, low ferritin flagging was far more prevalent, resulting in a ratio of 11.7 (0.95 confidence interval 11.2 to 12.1). Thus, men had an 11-fold higher theoretical relative sensitivity when detecting occult iron loss compared with women. System organ assessment is a basic clinical competence, and system organ classification for clinical biochemical tests could be used to organize clinical laboratory reports. The reference values provided should be biologically based, harmonized, and readily recognizable by the clinician to accurately guide decisions, in contrast to local procedural determinations. Examination of local laboratory data may reveal biased laboratory support. Full article

Background/Objectives: The increasing incidence of thyroid cancer in the United States suggests a possible role for environmental exposures that potentially alter thyroid hormone regulation through cellular toxicity. 2,4-Dichlorophenoxyacetic acid (2,4-D) is a commonly used herbicide that can act as an endocrine disruptor and may be toxic to the thyroid gland. This ecological study examined county-level associations of 2,4-D use and age-adjusted incidence of thyroid cancer in the United States. Methods: The study utilized age-adjusted incidence rates for thyroid cancer for 2017–2021 through the CDC database. County-level 2,4-D use data was obtained from the U.S. Geological Survey and averaged over two time periods: 2003–2007 (10-year lag) and 2008–2012 (5-year lag). The association between 2,4-D use and thyroid cancer incidence was tested using linear mixed effects models. We further stratified the data analyses by sex and rurality (using the Rural–Urban Continuum Codes, RUCC 6–9 codes). For this study, statistical significance was set at p < 0.05. Results: In nationwide analyses, no significant associations were found in combined (5-year lag: p = 0.218; 10-year lag: p = 0.276) and sex-stratified models (males: p = 0.540 and p = 0.497; females: p = 0.222 and p = 0.353, for the 5- and 10-year lags, respectively). In analyses limited to rural counties, 2,4-D exposure was significantly associated with greater thyroid cancer incidence for both the 5-year (p = 0.004) and 10-year (p = 0.006) lag periods for the total population. Conclusions: The strong associations observed in rural counties suggest that agricultural context may influence the observed relationship between county-level 2,4-D use and thyroid cancer incidence. Additional mechanistic and longitudinal studies are required to establish causality and to elucidate underlying endocrine pathways. Full article

Background: IL-15 is a promising cytokine for cancer immunotherapy. IL-15 promotes differentiation and homeostasis of innate and adaptive immune cells, and their cytolytic effector functions. The IL-15 receptor is composed of IL-15Rα, IL-15Rβ and the common γ_c chains. IL-15 is also trans-presented as IL-15Rα:IL-15 complex to IL-15Rβ:γ_c on neighboring cells. IL-15Rα is dispensable for early immune response to infections and in autoimmune diabetes. The role of IL-15Rα in antitumor immune responses remains unclear. Methods: In WT, Il15^−/− and Il15ra^−/− mice, we studied the growth of syngeneic tumor cell lines and tumor immune surveillance against endogenous fibrosarcoma induced by methylcholanthrene (MCA). Immune gene signature and total proteome analysis were performed on MCA-induced tumors. Results: Lack of IL-15 or IL-15Rα did not enhance the growth of implanted tumor cell lines, despite reduced immune cell infiltration. MCA-induced tumor incidence was reduced in mice lacking IL-15Rα but not IL-15, although both are required for efficient tumor immunoediting. Il15^−/− and Il15ra^−/− tumors showed reduced Ifng expression but displayed differential modulation of Ifng-responsive genes. Proteome profiles of Il15^−/− tumors, but not tumor-derived cell lines, showed significant reduction in antigen presentation pathways. B16-F10 melanoma cells expressing NLRC5, the IFNγ-induced transcriptional activator of tumor antigen presentation, still required IL-15 but not IL-15Rα for efficient tumor control. Conclusions: Our findings show that IL-15 plays a negligible role in immunosurveillance against spontaneous tumor development, whereas IL-15Rα restrains immunosurveillance. Neither IL-15 nor IL-15Rα have a significant impact on implanted tumor models, although IL-15 facilitates efficient control of highly immunogenic tumors for which IL-15Rα is dispensable. Full article

Background: Oral cancer remains a major global health concern, with increasing incidence and mortality, especially in developing countries. Public awareness is crucial for early detection and improved outcomes. Objective: To assess oral cancer awareness, recognition of risk factors and early signs, screening behavior, and care-seeking preferences among patients attending a university dental hospital in Türkiye. Methods: This cross-sectional, facility-based survey included 1360 volunteer patients who attended the Faculty of Dentistry between January and December 2025. Consecutive sampling was used to include all eligible and consenting individuals. A structured questionnaire assessed participants’ sociodemographic characteristics, oral cancer awareness, knowledge of symptoms and risk factors, screening history, and lifestyle habits. Data were analyzed using IBM SPSS Statistics 26.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics, chi-square tests, and multivariable logistic regression analyses were performed. Statistical significance was set at p < 0.05. Main outcomes and measures: The primary outcome was oral cancer awareness (measured by the question “Have you ever heard of oral cancer?”). Secondary outcomes included knowledge of risk factors and early clinical signs, screening history, preferred healthcare contact for suspected oral cancer, and lifestyle factors (tobacco and alcohol). Associations between sociodemographic variables and oral cancer awareness were also evaluated. Results: The sample consisted of 1360 participants (56.4% female; mean age: 33.44 ± 14.60 years; range: 18–70). Of the 1377 questionnaires collected, 1360 were complete and included in the final analysis (questionnaire completion rate: 98.8%). Breast cancer was the most recognized cancer (96.9%), whereas only 50.8% of participants had heard of oral cancer. Dentists (39.4%) were the primary source of information. Tobacco use (92.2%) and alcohol consumption (80.3%) were the most frequently identified risk factors, whereas only 58.3% recognized human papillomavirus as a risk factor for oral cancer. In univariate analyses, oral cancer awareness was significantly associated with age, marital status, education level, monthly income, occupation, alcohol use, and the timing of the most recent dental visit (p < 0.05). In multivariable logistic regression, undergraduate education (OR = 2.008, 95% CI: 1.135–3.553), higher monthly income (>100,000 TRY vs. <25,000 TRY, OR = 2.398, 95% CI: 1.571–3.658), alcohol use (OR = 1.521, 95% CI: 1.082–2.139), and a dental visit within the previous year (OR = 4.130, 95% CI: 1.590–10.730) remained independently associated with oral cancer awareness. Conclusions: Oral cancer awareness in this study population was limited. The findings suggest that targeted educational strategies may be beneficial for improving oral cancer awareness. Strengthening dentists’ preventive role and promoting education through social media may help improve oral cancer awareness and facilitate earlier detection. Full article

Background/Objective: Laparoscopic gastrectomy (LG) and robotic gastrectomy (RG) exhibit similar surgical outcomes in patients with gastric cancer (GC), except for the higher cost associated with RG. Comparative surgical outcome studies after open conversion from laparoscopic (OL) and robotic (OR) gastrectomy in GC are limited. This study aimed to evaluate clinical effectiveness while considering differences in procedural cost. Methods: This retrospective cohort study included a comparative analysis of patients with GC who underwent OL or OR. Inclusion criteria were histologically confirmed adenocarcinoma and curative resection for GC using OL or OR. Exclusion criteria included initially planned open surgery and other laparoscopic or robotic procedures without gastrectomy. Clinicopathological characteristics, as well as short- and long-term surgical outcomes, were compared between groups. Results: Overall, 118 (1.9%) of 6336 LG cases and 10 (2.6%) of 384 RG cases were included (p = 0.3308). Clinicopathological characteristics were statistically comparable between groups. Postoperative complication incidence, evaluated using the Clavien–Dindo classification, was 19.5% and 10% in the OL and OR groups, respectively (p > 0.05). The median hospital stay was 8 and 9.5 days in the OL and OR groups, respectively (p > 0.05). Reasons for open conversion were similar between groups and included adhesion, bleeding, advanced disease, and positive resection margins, among others. Overall 5-year survival was 0.79 (0.72–0.88) and 0.88 (0.67–1.0) in OL and OR, respectively (p = 0.596). Conclusions: Short- and long-term surgical outcomes after OL and OR did not differ statistically. Selection of LG versus RG should be performed with caution. Full article

Caloric restriction (CR), defined as a 30–60% decrease in ad libitum food intake without malnutrition, has emerged as one of the most robust non-pharmacological interventions for promoting metabolic health and longevity in various species, including yeast, worms, flies, rodents, and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer, and cardiovascular disorders) in mammals. Among the key organs influenced by CR, the pancreas—particularly the insulin-producing β-cells—plays a central role in maintaining glucose homeostasis and metabolic balance. A growing body of evidence suggests that CR exerts its beneficial effects, at least in part, through the modulation of nutrient-sensing pathways and epigenetic regulators. Sirtuins, a family of NAD⁺-dependent deacetylases and ADP-ribosyltransferases, have gained attention as pivotal molecular mediators of CR. By responding to changes in cellular energy status, sirtuins regulate diverse processes including gene expression, oxidative stress response, mitochondrial function, and autophagy. In the pancreas, sirtuins such as SIRT1, SIRT3, and SIRT6 have been implicated in preserving β-cell function, enhancing insulin secretion, and protecting against metabolic stress and inflammation. This review critically examines current evidence regarding the role of individual sirtuins in mediating the pancreatic response to caloric restriction, with particular emphasis on β-cell physiology, insulin secretion, mitochondrial function, autophagy, oxidative stress, and inflammatory signaling. We further discuss how these molecular mechanisms contribute to systemic metabolic homeostasis and may influence healthy longevity. Importantly, we integrate experimental findings with emerging clinical evidence demonstrating the recovery of β-cell function following dietary energy restriction and identify current controversies, limitations, and key knowledge gaps that should guide future translational research. Collectively, available evidence suggests that sirtuins represent central molecular links between caloric restriction and β-cell adaptation, highlighting their potential as therapeutic targets for preserving pancreatic function and preventing metabolic disease. Full article