Objectives: pH-responsive zeolite imidazolate framework-8 (ZIF-8) enables selective release of 5-fluorouracil (5-FU) within the acidic tumor microenvironment. However, the direct effects of ZIF-8 itself on cancer cells or surrounding tissues remain unclear. Since oral cancer involves interactions between epithelial tumor cells and stromal cells, comparing the effects of ZIF-8 on epithelial cancer cells and orofacial mesenchymal stem/stromal cells (OMSCs) is critical to understanding its broader biological impact. Methods: The effects of ZIF-8 on SCC7 epithelial cancer cells and OMSCs, including periodontal ligament stem cells (PDLSCs) and dental pulp stem cells (DPSCs), were evaluated using RNA sequencing, nuclear staining, live/dead assays, and immunocytochemistry. Cells were treated with 0, 1, 10, or 100 μg/mL ZIF-8. Based on nuclear staining results, live/dead viability assays were conducted on SCC7 and DPSCs treated with 0 or 100 μg/mL ZIF-8. Apoptosis-related markers (Bax, caspase-3, caspase-6, and caspase-10) were assessed following exposure to 100 μg/mL ZIF-8. Results: Transcriptomic analysis revealed that ZIF-8 not only facilitates selective 5-FU release but also directly induces apoptosis in SCC7 cells compared with 5-FU alone. At 100 μg/mL ZIF-8, SCC7 viability was significantly reduced, whereas OMSC viability was preserved. Nonviable SCC7 cells increased markedly compared with controls, while DPSCs showed no significant change. Apoptosis-related signaling was also elevated in SCC7 cells compared with DPSCs. Conclusions: ZIF-8 at 100 μg/mL selectively inhibits SCC7 growth while sparing OMSC viability and apoptosis.

Early detection of oral squamous cell carcinoma and oral potentially malignant disorders can improve survival. Although biopsy remains the diagnostic standard, less invasive adjunctive tests may help determine the need for further evaluation. This living systematic review assesses the impact and diagnostic test accuracy (DTA) of cytology as an adjunct to determine the need for biopsy or referral to detect oral potentially malignant disorders and oral squamous cell carcinoma among adults with or without lesions. The authors updated a 2017 systematic review. The authors conducted searches in MEDLINE, Epistemonikos, Embase, Cochrane Central Register of Controlled Trials through September 3, 2025. Pairs of reviewers independently conducted study selection, data extraction, and assessment of risk of bias. The authors prepared a summary of findings table and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. The authors included 36 studies evaluating cytology DTA in adults with lesions. The authors did not identify any randomized trials assessing the impact of cytology on person-important outcomes or studies in adults without lesions. Pooled DTA (7,038 lesions across 35 studies) had a sensitivity of 0.89 (95% CI, 0.83 to 0.92) and a specificity of 0.89 (95% CI, 0.84 to 0.93). The authors rated the certainty of the evidence as low due to risk of bias and indirectness. Cytology produces a large proportion of false-positive results. Although cytology had acceptable DTA, performance in practice may differ substantially due to serious concerns regarding risk of bias and indirectness of the evidence. When applied to adults with oral lesions, negative cytology may accurately identify healthy patients, reducing unnecessary referrals and biopsies. However, cytology may produce a considerable proportion of false-positive results, leading to unnecessary biopsies and patient anxiety and stress.