Scientia Pharmaceutica

Background/Objectives: Obesity is a multifactorial chronic disease involving adipose tissue dysfunction, low-grade inflammation, oxidative stress, mitochondrial dysfunction, and insulin resistance, contributing to type 2 diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, cardiovascular disease, and other complications. Piceatannol (3,3′,4,5′-tetrahydroxystilbene), a naturally occurring stilbene related to resveratrol, has attracted interest for its potential to modulate these interconnected processes. This narrative review critically synthesizes mechanistic, pharmacokinetic, preclinical, clinical, and translational evidence concerning piceatannol in adipose tissue dysfunction, metabolic inflammation, and insulin resistance and identifies major knowledge gaps and research priorities. Methods: PubMed/MEDLINE, Scopus, Web of Science Core Collection, and Google Scholar were searched from inception through 31 August 2026 for in vitro, animal, and human studies examining piceatannol in obesity, adipose tissue biology, inflammation, oxidative stress, glucose and lipid metabolism, insulin resistance, pharmacokinetics, and bioavailability. Evidence was synthesized using a structured narrative approach, with relevant SANRA quality-assessment domains considered during manuscript preparation and critical appraisal. Results: Piceatannol modulates multiple mechanisms implicated in obesity-associated metabolic dysfunction. In vitro studies demonstrate suppression of adipogenesis, attenuation of inflammatory and oxidative responses, and improvement in adipocyte metabolism and insulin signaling through pathways including AMPK, SIRT1, NF-κB, PI3K/Akt, MAPKs, and PPARγ. Selected animal studies have reported improvements in specific measures of weight gain, adiposity, hepatic lipid accumulation, glucose regulation, and inflammatory or oxidative markers; however, these findings vary across models and endpoints and have not been consistently replicated. A limited number of direct experimental comparisons have identified differences between piceatannol and resveratrol in selected biological endpoints. However, these findings are specific to the investigated models and experimental conditions and do not establish overall superiority in antioxidant, anti-inflammatory, or metabolic activity. No direct clinical comparisons are currently available to establish relative efficacy or safety. Preliminary randomized clinical studies using purified piceatannol have reported improvements in insulin resistance indices and blood pressure in selected populations, although findings remain inconsistent across metabolic outcomes. Studies involving piceatannol-rich passion fruit seed extracts have also reported beneficial effects on selected health-related outcomes; however, these effects cannot be attributed exclusively to piceatannol because of the presence of other bioactive constituents. Overall, human evidence remains limited by small sample sizes, heterogeneous study designs, and short intervention durations. Limited oral bioavailability and extensive phase II metabolism further constrain translation, while preliminary formulation studies suggest improvements in selected physicochemical or preclinical absorption parameters without establishing enhanced human systemic exposure, target-tissue delivery, or clinical efficacy. Conclusions: Piceatannol is a naturally occurring stilbene with experimentally observed biological activities relevant to several pathways implicated in obesity-associated metabolic dysfunction. Although cellular studies provide mechanistic and functional evidence, animal investigations remain relatively few and heterogeneous, with variable effects across metabolic outcomes. Preliminary human studies have reported changes in selected cardiometabolic and molecular biomarkers, but these findings do not establish clinically meaningful anti-obesity efficacy or superiority over resveratrol. Future research should prioritize standardized formulations, pharmacokinetic and dose–response characterization, independent preclinical replication, long-term safety evaluation, and adequately powered randomized controlled trials assessing clinically relevant metabolic outcomes.

The Endothelial Protein C Receptor (EPCR) is a transmembrane glycoprotein expressed on vascular endothelial cells. In cerebral malaria, binding of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants containing CIDRα1 domains can interfere with these protective interactions. We used virtual screening, molecular docking, MD simulations, and normal mode analysis to assess 87,489 natural compounds from the ZINC database. ZINC04084408, ZINC04084805, and ZINC04085245 were prioritized as candidate EPCR-binding compounds through the computational workflow. Their predicted poses generate hypotheses for experimental evaluation but do not establish inhibition of PfEMP1–EPCR interaction, effects on protein C activation or activated protein C (APC)-mediated signaling, or therapeutic efficacy. Following AutoDock Vina screening, ten compounds shared the lowest reported docking score of −13.9 kcal/mol and were advanced for detailed AutoDock 4.1 docking and pharmacokinetic evaluation. ZINC04084408, ZINC04084805, and ZINC04085245 were subsequently prioritized based on selected physicochemical and pharmacokinetic criteria. These compounds were predicted to occupy the hydrophobic ligand-binding pocket of EPCR. However, the calculations do not demonstrate selective EPCR binding or competitive inhibition of the PfEMP1–EPCR interaction. The predicted low aqueous solubility and model-dependent toxicity results represent important development limitations. The three compounds remain computationally prioritized candidates requiring experimental binding, toxicological, and functional validation.

Cucurbitacin B (CucB) has anti-inflammatory potential, but poor aqueous solubility and permeability limit its oral development. This study developed and evaluated a Soluplus^®-stabilized CucB nanosuspension (CucB-NS). The formulation was prepared by antisolvent precipitation, optimized using a Box–Behnken design, and evaluated for physicochemical properties, dissolution, ex vivo permeation, pharmacokinetics, anti-arthritic efficacy, safety, and stability. The optimized formulation had a particle size of 201.12 ± 2.21 nm, polydispersity index of 0.115 ± 0.023, zeta potential of −19.89 ± 1.89 mV, and desirability of 0.981. Compared with pure CucB, it increased saturation solubility from 5.6 ± 1.3 to 18.5 ± 1.5 µg/mL, 24 h dissolution from 29.89 ± 4.32% to 61.93 ± 2.45%, and 16 h permeation from 26.5 ± 3.4% to 48.9 ± 5.8%. Oral administration increased C_max from 35.55 ± 2.66 to 116.59 ± 5.25 ng/mL and AUC_0–∞ from 184.46 ± 10.49 to 1266.79 ± 54.24 ng·h/mL, yielding 686.75 ± 8.01% relative bioavailability without altering T_max. In FCA-induced arthritis, CucB-NS reduced clinical and synovial inflammatory outcomes and improved joint histology. No overt toxicity was observed, and physical stability was maintained for 3 months at 4 ± 2 °C. CucB-NS improved oral exposure and anti-arthritic activity, supporting further preclinical development.