Search Results (1,372)

Background/Objectives: The obesogenic environment is a key factor in the rising prevalence of metabolic syndrome (MetS), a major global public health challenge. Mangiferin (Mgf) is a C-glycosylated xanthone, and its preventive and therapeutic potential stems from its multisystemic pharmacological profile. This review integrates findings on Mgf in the management of metabolic syndrome, aiming to identify gaps and propose prospective studies to enable the scaling up of Mgf for clinical applications. Methods: To this end, a literature search was conducted, the level of evidence was identified, and the available scientific information on Mgf in metabolic syndrome was synthesized from PubMed, Scopus, and Web of Science from 2016 to 2025. Results: Mgf improves overall metabolic dysfunction by activating the AMPK pathway, reduces inflammation by activating Nrf2, suppressing NF-κB, and decreasing pro-inflammatory mediators (COX-2, IL-6, NLRP3), modulates CB1 and PPAR receptors and other markers associated with obesity (adiponectin, leptin, resistin), as well as autophagy processes. However, most of the evidence comes from in silico, in vitro, and preclinical studies, with few clinical observations. Conclusions: This underscores the need to integrate studies on the correlation between the bioavailability of Mgf and norathyriol with the regulation of the microbiota, as well as their effects on metabolomic and epigenetic mechanisms in MetS. Full article

High-fat diet (HFD)-induced hyperlipidemia is an experimental metabolic condition characterized primarily by dysregulated serum lipid levels and hepatic lipid accumulation, with associated oxidative, inflammatory, mitochondrial, and cardiovascular alterations. This study investigated the therapeutic efficacy of epigallocatechin gallate (EGCG)-functionalized selenium nanoparticles (EGCG-SeNPs) against HFD-induced metabolic and hepatic injury, in comparison with free EGCG, sodium selenite (Na₂SeO₃), and Lipanthyl. EGCG-SeNPs were characterized by dynamic light scattering, zeta potential analysis, transmission electron microscopy, X-ray diffraction, and UV–visible spectrophotometry. Forty-two adult male rats were allocated into six groups: control, HFD, HFD/Lipanthyl, HFD/EGCG, HFD/Na₂SeO₃, and HFD/EGCG-SeNPs. High-fat diet (HFD) feeding induced pronounced dyslipidemia, elevated hepatic enzymes, increased cardiac injury biomarkers, enhanced lipid peroxidation and nitrosative stress, depletion of antioxidant defenses, and disruption of the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) regulatory axis. HFD also increased nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), while altering mitochondrial apoptotic markers, including B-cell lymphoma 2 (Bcl-2), cytochrome c, and caspase-3. At the transcriptional level, HFD increased lipogenic gene expression and reduced the expression of genes related to fatty-acid oxidation, metabolic regulation, and mitochondrial homeostasis. EGCG-SeNPs showed the greatest overall improvement among the tested interventions, as indicated by an improved lipid profile, hepato-cardiac injury biomarkers, antioxidant status, inflammatory markers, apoptotic markers, hepatic architecture, and Nrf2 immunoreactivity. Collectively, EGCG-SeNPs may mitigate HFD-induced hepatic lipotoxicity and associated cardiac stress through coordinated modulation of lipid metabolism, redox balance, inflammation, and mitochondrial homeostasis. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive and antiangiogenic therapies, and identifying specific risk factors for recurrence remains a significant clinical challenge. This study aimed to evaluate the clinical characteristics and independent risk factors for recurrence in a large-scale cohort of MRONJ patients. Methods: This single-center retrospective study analyzed 812 patients diagnosed with MRONJ according to the 2022 AAOMS criteria at Chosun University Dental Hospital between 2020 and 2024. Demographic, clinical, radiographic, and medication-related variables were collected. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with recurrence. Results: The majority of patients were female (89.9%), with a mean age of 72.9 years, and mandibular involvement was most frequent (70.8%). Tooth extraction was the most common local precipitating factor (47.0%). The overall recurrence rate was 10.1%. Multivariate analysis identified bilateral jaw involvement (OR = 4.555, p = 0.006), mandibular ramus involvement (OR = 8.222, p = 0.008), and systemic liver disease (OR = 3.703, p = 0.037) as significant independent risk factors. Conversely, routes of prior antiresorptive medication administration involving intravenous-only or combined oral/intravenous therapy, as well as hyperlipidemia and a history of dental implant surgery, were associated with lower recurrence rates. Conclusions: Anatomical complexity and systemic health status are critical predictors of MRONJ recurrence. Patients presenting with bilateral or mandibular ramus involvement, or with compromised liver function, require more aggressive surgical debridement and individualized treatment planning to reduce the risk of recurrence. Given the small affected subgroups, the effect sizes for mandibular ramus involvement and liver disease should be interpreted with caution. Full article

Background: Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with over 75% of deaths occurring in low- and middle-income countries, where conventional risk models often demonstrate poor calibration and limited generalizability. Objective: This study aimed to develop an interpretable, pharmacotherapy-informed machine learning model for cardiovascular risk prediction using national electronic health record (EHR) data from Jordan. Methods: A retrospective cohort study was conducted using approximately 600,000 individuals from the national Hakeem EHR system (2018–2022). Demographic, clinical, blood pressure, laboratory, and medication data were integrated to construct three datasets reflecting varying levels of feature completeness. Multiple machine learning models were benchmarked, followed by optimization, hybrid modeling, and probability calibration. Model interpretability was assessed using SHAP analysis. Results: The national cohort demonstrated a high cardiometabolic burden, with prevalence of hypertension (50.2%), hyperlipidemia (54.9%), and diabetes (47.9%). Antihypertensive and lipid-lowering therapies were more frequently used among CVD patients (56.9% and 49.6%, respectively). Treatment patterns were dominated by amlodipine (19.9%) and atorvastatin (74.4%). The final calibrated seed-bagged gradient boosting model achieved robust performance (ROC-AUC 0.844; PR-AUC 0.813) with consistent generalization across datasets. Key predictors included antihyperlipidemic therapy, systolic blood pressure variability, age, and sex. Conclusions: This study presents JoRisk, a calibrated and interpretable machine learning framework that integrates pharmacotherapy and clinical data for short-term cardiovascular risk prediction. The model demonstrates strong performance using routinely available EHR variables and offers a scalable decision-support tool for risk stratification in resource-constrained healthcare systems. Full article

The human APOE gene is polymorphic with three major alleles that encode apolipoprotein (apo) E2, apoE3, and apoE4. Both apoE2 and apoE4 are associated with increased atherosclerosis risk. This study utilized human APOE2, APOE3, and APOE4 gene replacement mice and single-cell RNA sequencing approach to delineate the mechanisms underlying this association. The human APOE2, APOE3, and APOE4 mice were fed a Western-type high fat–cholesterol diet for 16 weeks. Hyperlipidemia and significant atherosclerosis were observed in APOE2 mice but not in APOE3 or APOE4 mice. However, increased vascular inflammation was observed in both APOE2 and APOE4 mice. Single-cell RNA sequencing followed by cluster analysis identified 25 major cell types in the aorta that include various immune cell types, endothelial cells, and various vascular mural cell subsets. Results showed that cells from the APOE2 mice were enriched with genes associated with intracellular lipid accumulation and inflammation, whereas cells from the APOE4 mice displayed elevated oxidative- and/or endoplasmic reticulum-stress and inflammatory response. Thus, apoE2 accelerates atherosclerosis by inducing diet-induced hyperlipidemia and inflammation, while apoE4 does not induce hyperlipidemia but enhances inflammation that may prime the vasculature for atherosclerosis development. The distinct mechanisms by which apoE2 and apoE4 promote atherosclerosis underscore the importance of including apoE genotype information in the design of therapeutics for atherosclerosis intervention. Full article

Background/Objectives: The accurate prediction of postprocedural mortality is critical for clinical decision-making; however, research on mortality risk models for patients undergoing mechanical thrombectomy remains limited. This study aimed to develop and validate machine learning models for predicting 90-day post-mechanical thrombectomy mortality. Methods: A retrospective-prospective cohort study involving 699 retrospective patients (January 2019–December 2022) and 274 prospective patients (January 2023–June 2024) from a single institution in Sichuan was conducted. The primary outcome was all-cause mortality within 90 days, ascertained via telephone follow-up. Predictors were identified using univariate analysis and LASSO regression. Eight predictive models were developed and evaluated using existing machine learning methods via 10-fold cross-validation. Model performance was assessed through discrimination, calibration, decision curve analysis, and interpretability via Shapley additive explanations. Results: The final dataset included 593 patients in the modeling set and 247 in the validation set. The 90-day mortality rates were 25.6% and 32.0%, respectively. Key predictors included age, hyperlipidemia, atrial fibrillation, pre-stroke statin use, antiplatelet/anticoagulant therapy within 48 h of onset, dysphagia, D-dimer levels, and activities of daily living scores. Logistic regression demonstrated superior performance in the modeling cohort (AUC = 0.87), whereas the multilayer perceptron model exhibited the greatest efficacy in the validation cohort (AUC = 0.77). Conclusions: Machine learning algorithms can accurately predict 90-day mortality among patients undergoing mechanical thrombectomy. The multilayer perceptron model demonstrated robust validation performance and offers a potential tool for personalized risk assessment and optimization of clinical decision-making. Full article

Background and Objectives: Type 2 diabetes mellitus (T2DM) causes retinal microvascular changes that precede clinically apparent diabetic retinopathy (DR). We aimed to identify which optical coherence tomography angiography (OCTA) biomarkers best distinguish eyes with T2DM without clinical DR from healthy controls and to evaluate machine learning classifiers trained on a comprehensive 68-parameter OCTA panel. Materials and Methods: In this prospective case–control study, 80 patients with T2DM without clinical DR and 33 controls underwent 3 × 3 mm macular OCTA using an Optovue RTVue Avanti System. After outlier screening, 221 eyes (155 T2DM, 66 controls) were analyzed. Sixty-eight OCTA parameters were extracted, covering FAZ morphometry (including foveal density FD-300), SCP and DCP vessel density and layer thickness, outer-retina and choriocapillaris flow, and a full retinal-thickness map. Between-group comparisons used the Mann–Whitney U test with Benjamini–Hochberg FDR correction. Logistic regression, random forest, and XGBoost classifiers were evaluated with patient-grouped 10-fold cross-validation; feature importance was quantified via SHAP. Results: Forty-two of 68 parameters reached FDR significance (q < 0.05). Deep capillary plexus vessel density was the most discriminative family (whole image rb = −0.66, q = 2.5 × 10⁻¹³; parafovea rb = −0.64). FD-300 was reduced in T2DM (median 47.55% vs. 51.86%; rb = −0.57; q = 1.0 × 10⁻¹⁰) and emerged as the top SHAP feature (mean |SHAP| = 0.81). FAZ circularity decreased without FAZ-area enlargement, and outer-retina flow was paradoxically elevated (rb = +0.39), consistent with a projection artifact. XGBoost using all 68 features achieved a patient-grouped cross-validated AUC of approximately 0.91, compared with 0.85 for conventional SCP + DCP whole-image density. No parameter correlated with current HbA1c in T2DM (all q > 0.98), and the well-controlled (<7%) and poorly controlled (≥7%) subgroups were indistinguishable across five of six principal biomarkers, consistent with metabolic memory. FD-300 remained independent after adjustment for hypertension, hyperlipidemia, and age (OR = 0.76; 95% CI 0.69–0.84; p < 0.001). Conclusions: A multi-compartment OCTA panel outperforms conventional two-layer vessel-density metrics in detecting preclinical diabetic microvasculopathy, although external validation is required before clinical use. FD-300 is the single most informative biomarker, while choriocapillaris and retinal thickness measures provide complementary, compartment-specific signals. Because the OCTA signature is decoupled from the current HbA1c, screening should not be deferred in well-controlled T2DM. Full article

Background/Objectives: Metabolic syndrome (MetS) is a pressing global health challenge comprising obesity, hyperglycemia, hypertension, and hyperlipidemia. Conventional polypharmacy often presents long-term compliance issues and side effects. Eucommia ulmoides Oliv., a traditional medicinal and edible plant rich in iridoids, lignans, flavonoids, and polysaccharides, has emerged as a promising natural intervention. This review aims to systematically summarize the bioavailability and multifaceted pharmacological mechanisms of E. ulmoides and its bioactive components in alleviating MetS. Methods: We comprehensively reviewed the recent in vitro and in vivo literature to map the functional evidence, specific signaling pathways, and gut microbiota–host interactions associated with E. ulmoides extracts and its key phytochemicals (e.g., asperuloside) against various metabolic dysfunctions. Results: Current evidence indicates that E. ulmoides operates through a “multi-component, multi-target, and multi-pathway” paradigm. For hyperlipidemia and obesity, it activates hepatic lipid metabolism (PPARα/CPT1A, FXR/CYP7A1) and mitigates oxidative stress (Nrf2/ARE). Furthermore, it dose-dependently reshapes the gut microbiota by enriching beneficial bacteria like Akkermansia and increasing butyrate production, exerting profound gut–liver axis regulation. It also ameliorates hypertension by activating the ACE2-Ang-(1–7)-Mas axis, improves insulin resistance via the AMPK/PI3K/Akt cascade, and manages hyperuricemia by modulating XOD and renal transporters. Notably, the low oral bioavailability of its glycosides highlights the crucial role of gut microbial hydrolysis in its efficacy. Conclusions: E. ulmoides holds substantial therapeutic potential as a multi-target natural supplement for MetS. However, future translational applications necessitate large-scale randomized clinical trials, multi-omics studies to further clarify host–microbiome interactions, and the development of standardized formulations to ensure clinical efficacy. Full article

Background: The Keystone Island Perforator Flap (KIPF) is a well-established reconstructive option for defect closures but poses challenges in regions with limited skin laxity, such as the pretibial region. This often leads to impaired wound healing and subpar cosmetic results. We examine a modified approach incorporating the fascial release technique to observe both functional and aesthetic outcomes. Methods: A retrospective review was conducted of 20 adult patients who underwent pretibial reconstruction with the modified KIPF at a single institution. All procedures were performed in an office setting under local anesthesia. Data on demographics, comorbidities, flap size, and postoperative outcomes was collected. Results: Patients ranged from 46 to 91 years of age (mean 69). The majority (60%) were female and nonsmokers (90%). Common comorbidities included hypertension (45%), hyperlipidemia (25%), and diabetes (10%). Most procedures (90%) were performed following oncologic excisions. Defect sizes ranged from 1.95 to 17.5 cm². No intraoperative flap failures were seen. Two patients developed minor wound dehiscence, both managed conservatively. Complete wound healing was often seen within one month. Conclusion: The modified KIPF provides a safe, reliable method of pretibial reconstruction. Its low complication rate and feasibility under local anesthesia support its expanded use in anatomically constrained regions. Full article

Background: Obesity is closely associated with gut microbiota dysbiosis. Nervonic acid (NA; (15Z)-15-tetracosenoic acid) is a bioactive fatty acid with reported metabolic effects. This study aimed to investigate the associations between NA administration, gut microbiota composition changes, and host metabolic phenotypes in high-fat diet (HFD)-fed mice. Methods: C57BL/6J mice were fed an HFD for 12 weeks and concurrently administered NA at doses of 20, 40, and 60 mg/(kg·d) by gavage. Metabolic parameters, histopathological changes, and fecal microbiota composition (via 16S rRNA gene sequencing) were evaluated. Results: NA administration was associated with significantly attenuated HFD-induced increases in body weight and adipose tissue mass, as well as marked reductions in serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol (all p < 0.05). Hepatic steatosis and adipose tissue inflammation were also attenuated. 16S rRNA gene sequencing revealed that NA was associated with the counteraction of HFD-induced gut microbiota dysbiosis, including alterations in α-diversity and community structure. NA was associated with higher relative abundances of taxa such as Blautia, Oscillibacter, Faecalibaculum, Parabacteroides, Dubosiella, and Odoribacter and lower relative abundances of Lachnoclostridium, Mucispirillum, and Alistipes. Within-group correlation analyses showed that genera with higher relative abundances were inversely associated with lipid parameters and adiposity, whereas genera with lower relative abundances correlated positively with these metabolic indicators. Conclusions: NA administration was associated with bidirectional changes in gut microbiota composition—the enrichment of certain taxa and the suppression of others—concomitant with the amelioration of HFD-induced metabolic dysfunction. These findings indicate correlations between NA, gut microbiota alterations, and improved metabolic phenotypes; however, causality remains to be established. Full article

Buttock claudication after endovascular aneurysm repair (EVAR) impairs recovery and quality of life, yet individualized preoperative risk tools are scarce. We conducted a retrospective dual-center cohort study of consecutive EVAR patients from Fuxing and Xuanwu Hospitals. The endpoint was new-onset postoperative buttock claudication. Missingness was quantified for each predictor and handled using complete-case analysis or model-based single imputation according to the extent of missingness. Data were split into training and held-out test sets at a 70:30 ratio with outcome stratification. Predictor screening, preprocessing, and hyperparameter tuning were performed within the training/resampling framework to minimize data leakage. Ten algorithms were tuned using stratified 10-fold cross-validation, and test set performance was assessed using discrimination, threshold-based metrics, calibration plots, calibration intercept/slope, Brier score, and decision-curve analysis. SHapley Additive exPlanations (SHAP) provided model-agnostic explanations. A web calculator was deployed. Among 272 patients, 71 (26.1%) developed claudication. Independent risk factors included aneurysm with iliac involvement (adjusted OR 4.04), male sex (3.26), unilateral (3.86) and bilateral internal iliac artery embolization (8.61), and hyperlipidemia (5.66); >2 distal internal iliac branches was protective (0.15). On the test set, the neural network achieved the highest AUROC (test ROC), with the highest sensitivity (0.810) and top F1 (0.557) at balanced specificity (0.617); CatBoost maximized accuracy (0.790) and specificity (0.900). Calibration was acceptable, and DCA showed positive net benefit across clinically plausible thresholds. SHAP confirmed physiologic directions and enabled case-level interpretation. An explainable machine learning framework accurately stratifies risk of buttock claudication after EVAR, highlighting the roles of internal iliac embolization, iliac involvement, and distal branch anatomy. The publicly available Shiny tool supports perfusion-aware planning and shared decision-making. Full article

Background: The fruits of Rosa laxa Retz. (FRL) is a traditional medicinal and edible fruit widely used in Xinjiang for its potential health benefits. Its chemical variations across geographical origins remain poorly understood, as do the molecular mechanisms underlying its anti-hyperlipidemic effects. This study aimed to characterize the chemical profile of FRL extract (FRLE) from different origins, identify its bioactive constituents and metabolites in vivo, and evaluate its efficacy and potential mechanisms against HLP. Methods: UPLC-QTOF-MS was employed for qualitative and quantitative profiling, combined with PCA to differentiate samples from five origins. An HLP mouse model was established to evaluate the pharmacodynamic effects, while acute and sub-chronic toxicity tests assessed safety. Serum pharmacochemistry was used to track absorbed constituents and metabolites. Finally, network pharmacology, molecular docking, and Western blot were integrated to elucidate the underlying mechanisms. Results: A total of 60 compounds were identified in FRLE, with 20 key components quantified via the TOF-MRM mode. PCA indicated that the Yamalike Mountain samples possessed the most diverse chemical profile and the highest response of active markers. Pharmacodynamic results showed that FRLE (extraction yield 24.19%) significantly improved TC, LDL-C, and corrected abnormal HDL-C levels in HLP mice, while H&E staining confirmed the alleviation of hepatic steatosis. Safety evaluations revealed no significant acute or cumulative toxicity at the maximum feasible dose of 16.6 g/kg. In rat plasma, 15 prototypes and 14 metabolites were identified. FRLE acted on the “Lipid and Atherosclerosis” pathway by modulating key targets, including NFE2L2, CYP1A1, NOS3, and MAPK1. Conclusions: Our findings demonstrate that FRLE is a safe and effective candidate for the management of hyperlipidemia. This study establishes a link between the material basis and biological mechanisms of FRL, thereby providing a scientific foundation for its further resource development and clinical application. Full article

Background/Objectives: Atherosclerosis is a multifaceted inflammatory condition closely linked to immunonutritional status. The C-reactive protein–albumin–lymphocyte (CALLY) index is a composite marker of immunonutrition. We assessed the relationship between this index, age, and carotid stenosis in individuals undergoing carotid Doppler ultrasonography. Methods: Individuals who underwent routine carotid Doppler ultrasonography were retrospectively analyzed. Carotid stenosis was categorized by severity, and bilateral intima–media thickness was recorded. The composite index integrating C-reactive protein, albumin, and lymphocyte parameters was derived from laboratory parameters. Traditional cardiovascular risk factors, including hypertension, diabetes mellitus, hyperlipidemia, and smoking status, were also recorded and incorporated into multivariable analyses. Sex-related differences were additionally evaluated using sex-stratified correlation analyses. Results: Among 1516 patients, 895 (59.1%) were younger than 65 years and 621 (40.9%) were aged 65 years and above. Carotid artery stenosis and intima–media thickness were significantly higher in individuals aged 65 years and above. The mean index value was significantly lower in the older group (4.0 versus 8.3; p < 0.001). Hypertension, diabetes mellitus, and hyperlipidemia were significantly more prevalent in patients with carotid stenosis (p < 0.001 for all), whereas smoking was not associated (p > 0.05). Male sex was independently associated with carotid stenosis, and sex-stratified analyses demonstrated similar inverse associations between age and CALLY index values in both sexes. In multivariable analysis, lower index values were independently associated with carotid stenosis and carotid intima–media thickness in both age groups. In the overall cohort, the index demonstrated moderate discriminatory performance (area under the curve = 0.724). Similar moderate performance was observed in the <65 (AUC = 0.681) and ≥65 (AUC = 0.685) subgroups. Conclusions: The CALLY index was independently associated with carotid stenosis and CIMT after adjustment for traditional cardiovascular risk factors. Although effect sizes were comparable between age groups, CALLY index levels were lower in older individuals. These findings suggest that the CALLY index may provide complementary information in the assessment of carotid atherosclerosis, particularly in elderly populations. However, given the retrospective cross-sectional design and moderate discriminatory performance, it should not be interpreted as a standalone, causal, or disease-specific marker. Full article

Background: The use of estrogen-based gender-affirming hormone therapy (E-GAHT) has been associated with an increased risk of venous thromboembolism (VTE), but much of the evidence originates from data on cisgender women and from cohorts of transgender and gender diverse (TGD) individuals treated with older estrogen or estrogen/progesterone preparations, often at higher doses. Data on VTE risks associated with more modern E-GAHT regimens in TGD populations are scarce. Methods: A retrospective cohort study of adult TGD individuals who received E-GAHT within the Duke University Health System between January 1996 and June 2025 was conducted. The Duke Enterprise Data Unified Content Explorer (DEDUCE), a Duke electronic medical record search tool, was utilized to identify a cohort of TGD individuals who were prescribed E-GAHT. From this cohort, individuals who experienced a VTE during E-GAHT exposure were identified. Demographic characteristics and comorbidities were compared between the overall study cohort and those who experienced VTE using the SlicerDicer tool within Epic, supplemented by manual chart review. Results: Among 1173 adult TGD individuals prescribed E-GAHT, 16 (1.4%) experienced a VTE. Of these, 11 (68.8%) experienced a pulmonary embolism (PE with/without deep vein thrombosis [DVT]) and five (31.3%) experienced a DVT alone. Among the 16 patients with VTE, six (37.5%) had a transient surgical risk factor prior to VTE, three (18%) had significant non-surgical risk factors, and one (6%) had cancer. The remaining six (37.5%) patients experienced an unprovoked VTE. Patients with VTE were significantly older than the general population of TGD adults and were significantly more likely to experience hypertension, hyperlipidemia, and type 2 diabetes mellitus, compared to TGD patients without VTE. Conclusions: In this retrospective cohort, the proportion of TGD individuals on E-GAHT with VTE was lower than previously reported in the literature. Most events occurred in the presence of other established risk factors, suggesting that E-GAHT itself may confer a lower VTE risk than previously assumed. Larger prospective studies that evaluate both estrogen-specific and patient-specific risk factors are needed to clarify VTE risk in this population. Full article

Oral squamous cell carcinoma (OSCC), comprising ~90% of oral malignancies, remains a major global health burden with rising incidence despite declining tobacco use. While tobacco and alcohol are classic dominant risk factors, a distinct subgroup of nonsmoking, nondrinking (NSND) patients is increasingly recognized, accounting for 15–35% of OSCC cases in many cohorts, particularly in developed countries. This emerging epidemic shows striking demographic patterns: strong female predominance (often 65–77% of cases), bimodal age distribution with peaks in young adults (<45 years) and elderly individuals (>70 years), and overrepresentation among non-Hispanic White and certain Asian populations. Unlike traditional habit-related OSCC, which favors the floor of the mouth in older males, NSND tumors predominantly arise on the lateral tongue, gingiva, and buccal mucosa. Etiopathogenesis extends far beyond conventional carcinogens and involves multifactorial mechanisms, including chronic mechanical irritation from dental factors, oral microbiome dysbiosis enriched with periodontal pathogens (e.g., Fusobacterium nucleatum and Porphyromonas gingivalis), limited roles for viruses (minimal HPV contribution, possible EBV or “hit-and-run” HSV effects), genetic susceptibilities (e.g., Fanconi anemia and CDKN2A mutations), epigenetic changes, hormonal influences contributing to female bias, metabolic conditions (diabetes and hyperlipidemia), poor oral hygiene, and chronic inflammation. NSND OSCC frequently exhibits a distinct immunological profile with higher tumor-infiltrating lymphocytes and PD-L1 expression, potentially favoring immunotherapy, though prognosis remains heterogeneous—better in some cohorts due to fewer comorbidities, yet worse in young patients with higher recurrence and second primary tumor risks. Delayed diagnosis is common due to low suspicion in “low-risk” individuals. This review underscores NSND OSCC as a unique entity requiring expanded risk assessment, heightened clinical vigilance for persistent oral lesions regardless of habit history, and targeted research into novel prevention and therapeutic strategies. Full article