The scale of the problem the review addresses is substantial. In 2022, 2.5 billion adults worldwide were graded as overweight, including 890 million adults living with obesity, representing 16 percent of the global adult population. Current trends cited in the paper suggest that by 2030 roughly half of the global adult population will be overweight, with 17 percent of men and 22 percent of women expected to have obesity. In 2021, overweight and obesity caused approximately 3.7 million deaths from noncommunicable diseases such as diabetes and cancer. The World Health Organization declared obesity a global epidemic in 1997, classifying it as a chronic disease rather than a lifestyle choice.

Existing pharmacotherapy is effective but constrained. Glucagon-like peptide-1 (GLP-1) and GLP-1/GIP receptor agonists such as semaglutide and tirzepatide have demonstrated significant efficacy in weight loss and metabolic benefits; in clinical trials, semaglutide and tirzepatide achieved average weight loss of approximately 15 percent and 20 percent, respectively. However, the review notes that the required lifelong medication is often limited by high economic costs and adverse effects, including gastrointestinal problems, potential micronutrient deficiencies and dehydration. Against this backdrop, the authors frame triterpenoids as potential adjunctive, complementary components rather than stand-alone competitors to standard pharmacotherapies.

Celastrol, a pentacyclic triterpene extracted from the roots of the thunder god vine (Tripterygium wilfordii), is presented as one of the most potent natural compounds investigated for the pharmacological treatment of obesity. Research in mouse models identified celastrol as a leptin sensitizer: it binds to and inhibits the protein tyrosine phosphatases PTP1B and TCPTP in the hypothalamus, which normally inhibit the leptin signaling cascade. In diet-induced obese C57BL/6J mice given 100 micrograms per kilogram per day for three weeks, this produced a 45 percent weight loss and roughly 75 percent less food intake, while restoring energy expenditure. The effect depends on leptin signaling, as celastrol was ineffective in leptin-deficient and leptin receptor-deficient mouse models, confirming its role as a true sensitizer rather than a nonspecific anorectic.

Ursolic acid, found naturally in apple skins, basil, peppermint, oregano and thyme, is highlighted for its potential to drive body recomposition. In a mouse model of diet-induced obesity, ursolic acid administration promoted simultaneous growth of skeletal muscle and brown adipose tissue by enhancing activation of the insulin-like growth factor 1 (IGF1)/Akt pathway. In skeletal muscle, activated Akt stimulates the mTOR signaling pathway to promote protein synthesis and muscle hypertrophy while inhibiting atrophy processes mediated by FoxO transcription factors. In brown adipose tissue, Akt signaling increases activity of Uncoupling Protein 1, which uncouples mitochondrial respiration from ATP synthesis and drives heat production, raising energy expenditure. In the summarized mouse studies, ursolic acid at 0.14 to 0.27 percent of the diet over six weeks significantly reduced total body weight, fasting blood glucose and liver weight while increasing skeletal muscle and brown adipose tissue mass.

The ginsenosides, a structurally heterogeneous group of triterpenoids derived from Panax plants, act on multiple fronts. The primary ginsenoside Rb1 activates browning of white adipose tissue by stimulating AMPK phosphorylation, upregulating UCP1, PPARγ and PGC-1α, and also stimulates cellular autophagy to degrade dysfunctional organelles and lipid droplets. Rg1 suppresses pancreatic lipase activity, thereby reducing fat absorption, and was verified in rat models to reduce hypothalamic oxidative stress signaling by promoting Nrf2-related pathways. Rg3 was identified as the most potent in mediating appetite control, stimulating GLP-1 secretion and thereby enhancing satiety signaling. Compound K, an intestinal microbiota metabolite of Rb1 with higher bioavailability than its parent compound, inhibits preadipocyte differentiation, attenuates fatty acid synthesis via AMPK activation and reduces oxidative stress. In high-fat-diet-induced obese mice and rats, treatment with Rg1, often combined with Rb1, effectively reduced body weight, blood lipids, body fat content and total food intake.

Oleanolic acid, an isomer of ursolic acid found in olive leaves and grape skins, shows anti-inflammatory effects in animal models of obesity, facilitating a macrophage phenotype switch from the pro-inflammatory M1 to the anti-inflammatory M2 state and lowering levels of interleukin-6 and tumor necrosis factor-alpha. It also inhibits adipocyte differentiation by suppressing C/EBPα and PPARγ expression, reduces fat accumulation in liver tissue, promotes skeletal muscle mass via PI3K/Akt signaling, and acts as a TGR5 agonist that increases energy expenditure and induces GLP-1 secretion. Notably, in vitro studies with human peripheral blood mononuclear cells showed that treatment with 1 microgram per milliliter of oleanolic acid for 24 to 72 hours enhanced telomerase activity by up to 5.9-fold, potentially slowing obesity-induced accelerated cellular senescence. The review stresses that these telomerase findings are limited to the in vitro system described, and further in vivo and human clinical studies are needed. Betulinic acid, meanwhile, reduced body weight by roughly 13 percent and abdominal fat accumulation about 1.6-fold in diet-induced obese mice over 11 weeks, with effects occurring independently of food intake, driven by strongly increased AMPK activity and downstream suppression of lipogenesis and adipogenesis gene expression.

Despite these striking preclinical results, the review is candid about the translation gap. Promising effects in rodent models often translate into no significant or only modest, inconsistent reductions in human body weight. Recent meta-analyses indicate that ursolic acid supplementation at standard doses does not significantly reduce body weight. Human studies on ginsenosides show only modest, often inconsistent reductions in body weight. Low oral bioavailability—stemming from poor solubility, low membrane permeability and rapid first-pass metabolism—is identified as the key bottleneck. Celastrol additionally carries a narrow therapeutic window; in mouse models, high doses have been associated with increased blood pressure and reduced physical activity. Clinical evidence specifically relevant to obesity is still in its early stages: a phase 1 study (NCT05494112) is underway to evaluate the safety and tolerability of celastrol in healthy individuals, with final results still being evaluated. The authors caution that historical clinical trials of celastrol in rheumatoid arthritis and psoriasis cannot be translated to obese humans because the metabolic mechanisms differ fundamentally.

To overcome these pharmacokinetic and safety limitations, the review surveys advanced delivery and production strategies. Nanotechnology-based systems have shown substantial gains in animal and cell models: PEG-PCL nanoparticles of celastrol produced a 4.6-fold increased area under the curve and 7.5-fold increased peak concentration in diet-induced obese mice, with less gastrointestinal toxicity than free celastrol; amorphous solid dispersions raised ursolic acid’s oral bioavailability 19-fold in rats; a self-nano-emulsified drug delivery system increased oleanolic acid’s oral bioavailability 2.4-fold; and a cyclodextrin-based nanocarrier enhanced betulinic acid’s plasma AUC 7.41-fold. Synthetic biology offers complementary routes, including sustainable bioproduction of celastrol via genetically modified Saccharomyces cerevisiae after researchers elucidated its complete plant biosynthetic pathway, and engineered probiotics that could biotransform primary ginsenosides in situ, decoupling production of active metabolites from human microbiota variability. The authors note these strategies face their own hurdles, including nanomaterial toxicity, regulatory barriers, genetic instability and long-term safety questions.

The review concludes that triterpenoids warrant attention as adjunctive components of obesity therapy, valued for their versatile multi-target mechanisms supporting metabolic health through long-term restoration, alongside established treatments. It also flags inherent risks of multi-target activity, including off-target interactions, narrow therapeutic windows and agent-specific toxicities, as well as drug-drug interaction potential through modulation of cytochrome P450 enzymes such as CYP1A2 and CYP3A4. Long-term safety data and human clinical trials remain extremely limited, and the authors call for systematic optimization of compound-specific pharmacokinetic profiles, standardized dosing protocols and expanded clinical testing before these compounds can be used effectively as therapeutic agents for human metabolic health and healthy aging.

Subject of Research: The potential of natural triterpenoids as multi-target compounds for obesity management and metabolic restoration

Article Title: Triterpenoids – future multi-target compounds against obesity and towards restoration of metabolic health

Article References: Becker, J., Ebert, B. E., Festel, G., & Blank, L. M. (2026). Triterpenoids – future multi-target compounds against obesity and towards restoration of metabolic health. Frontiers in Aging, 7, 1939566. https://doi.org/10.3389/fragi.2026.1939566

Image Credits: AI Generated

DOI: 10.3389/fragi.2026.1939566

Keywords: triterpenoids, obesity, celastrol, ursolic acid, ginsenosides, oleanolic acid, betulinic acid, metabolic health, leptin sensitivity, AMPK, oral bioavailability, healthy aging