The increasing and global distribution of microplastics and nanoplastics (MPs/NPs) in the environment has led to concern about their potential influence on human health, especially on the gastrointestinal tract, as well as the brain. MPs/NPs could traverse epithelial and endothelial barriers, disrupt the gut microbiota, and perturb the microbiota–gut–brain axis, leading to systemic inflammation and possibly extending neurodegenerative processes. Experimental models now demonstrate that MPs/NPs reprogram nuclear and mitochondrial epigenetics—DNA methylation, histone modifications, non-coding RNAs, and mitochondrial DNA regulation—in gut, immune, and neural cells with downstream effects on synaptic function, neuronal survival, and protein aggregation. This mechanistic narrative review integrates preclinical and emerging human evidence of how MPs/NPs compromise intestinal barrier integrity, modulate gut microbiota composition, affect the blood–brain barrier, and converge on oxidative stress, neuroinflammatory signaling, and cell death pathways within the central nervous system across key neurodegenerative diseases. Overall, the review offers an integrated model in which environmental exposure to chronic MPs/NPs disrupts the microbiota–gut–brain axis and drives concurrent nuclear and mitochondrial epigenetic remodeling, lowering the threshold for neurodegeneration in susceptible individuals, while outlining candidate mechanistic readouts that require exposure-specific validation in human-relevant models and longitudinal cohorts.

Cancer remains the second leading cause of mortality worldwide, underscoring the urgent need for novel therapeutic strategies. Drug repurposing is an effective strategy to address current cancer challenges, such as the resistance and toxicity associated with traditional chemotherapy. Among the various psychotropic drugs, antidepressants are emerging as promising candidates due to their demonstrated anticancer activity. We evaluated duloxetine (DUL), a serotonin-norepinephrine reuptake inhibitor, for anticancer and immunomodulatory activity by performing comprehensive in vitro and in vivo experiments. In HCT116 (colon), HeLa (cervical), and MDA-MB-231 (triple-negative breast cancer) human cancer cells, and 4T1 mouse breast cancer cells, we investigated DUL's cytotoxicity, apoptosis, autophagy, cell cycle arrest, and migration inhibition through MTT assay, flow cytometry, and immunofluorescence methods. An orthotopic mouse model of breast cancer was utilized to investigate the in vivo tumor inhibitory effects of DUL, along with its systemic toxicity and immunomodulatory properties. Gene expression (p53, Beclin-1), cytokine profile, and CD3⁺T cell activation were examined by mRNA sequencing and ELISA kits to explore underlying mechanisms. For the first time, our in vitro results indicated that DUL caused dose-dependent cytotoxicity, apoptosis, autophagy, and cell cycle arrest in all cancer lines tested, which was more selective than 5-fluorouracil (5-FU). Mechanistically, DUL modulated apoptotic (Bcl-2, Bax, caspase-3), autophagic (p62), and survival (pAkt) signaling, disrupted mitochondrial membrane potential, and inhibited cell migration. In vivo, DUL inhibited tumor growth without inducing hepatic or renal toxicity. Notably, DUL stimulated the production of pro-inflammatory cytokines (IFN-γ, IL-1β, TNF-α), enhanced the immunity of CD3⁺T cells, and increased the expression of pro-apoptotic p53 and autophagic Beclin-1 genes, reflecting its dual antitumor and immunomodulatory actions. Our findings revealed for the first time that DUL is a promising repurposed drug for cancer treatment, as it has demonstrated proven antitumor efficacy and immune-stimulating properties. This novel dual role of DUL warrants further investigation in clinical oncology.

Recent advances in enone chemistry have enabled the development of structurally optimized derivatives with improved anticancer selectivity. In this study, the cytotoxic activity and underlying mechanisms of sodium salts of four α,β-unsaturated enones (ES1–ES4), synthesized from vanillin-based scaffolds, were evaluated in human colorectal carcinoma (HCT-116), cervical adenocarcinoma (HeLa), and normal lung fibroblast (MRC-5) cell lines. All compounds exhibited concentration- and time-dependent cytotoxicity, with ES2 showing the highest potency (IC₅₀ = 14.25 μM in HCT-116 and 18.12 μM in HeLa at 72 h) and minimal toxicity toward MRC-5 cells (IC₅₀ > 90 μM). Although cisplatin demonstrated greater overall cytotoxicity, the enone salts displayed significantly higher selectivity indices, indicating a more favorable therapeutic window. Phase-contrast microscopy revealed characteristic morphological features of apoptosis, including cell rounding and membrane blebbing. Mechanistic investigations confirmed mitochondrial-mediated apoptosis, evidenced by increased early and late apoptotic populations, Bax upregulation, Bcl-2 downregulation, and caspase-3 activation. JC-10 staining demonstrated mitochondrial membrane depolarization accompanied by cytochrome c release. In addition, cell cycle analysis revealed pronounced G2/M phase arrest, particularly in HCT-116 cells. Collectively, these findings indicate that vanillin-derived enone sodium salts exert selective anticancer effects through mitochondrial apoptosis and cell cycle disruption, supporting their potential as low-toxicity anticancer candidates.