A Review on Gamma-Oryzanol as a Multitarget Therapeutic Agent for Metabolic Syndrome: Mechanisms, Preclinical Evidence, and Clinical Prospects

Metabolic syndrome (MetS) is a multifactorial disorder characterized by central obesity, insulin resistance, dyslipidemia, and hypertension, which collectively increase the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD). Due to the growing global burden of MetS, there is increasing interest in nutraceuticals such as gamma-oryzanol (γ-ORY), a bioactive compound derived from rice bran oil (RBO), as potential therapeutic agents. A systematic literature search was conducted through July 2024 using PubMed, Google Scholar, and SciFinder. The keyword "gamma-oryzanol" was combined with terms related to MetS and its components. Original preclinical and clinical studies were included, while reviews and book chapters were excluded; however, their references were screened for additional relevant studies. Preclinical studies indicate that γ-ORY targets multiple molecular pathways, including activation of AMP-activated protein kinase, upregulation of peroxisome proliferatoractivated receptor-α, inhibition of nuclear factor-κB, and promotion of glucose transporter type 4 translocation. These mechanisms collectively improve glucose and lipid metabolism, enhance insulin sensitivity, and reduce inflammation. Clinical trials, primarily involving adults with T2DM, obesity, dyslipidemia, or postmenopausal women (aged 30-70 years, mixed ethnicities), report that γ-ORY reduces total cholesterol (10-15%), LDL-C (8-12%), triglycerides (10-18%), fasting glucose (10-25 mg/dL), and HbA1c (0.3-0.8%). Compared to conventional therapies such as statins (LDL-C reduction: 30-50%) or antihypertensives (e.g., irbesartan), γ-ORY demonstrates milder efficacy but better tolerability, and may enhance the antihypertensive effects of irbesartan. Notably, clinical studies consistently report a favorable safety profile for γ-ORY, with minimal adverse effects and no major safety concerns to date. Overall, γ-ORY shows promise as a safe, multitarget nutraceutical for MetS management, with antioxidant, anti-inflammatory, and lipid-lowering properties. However, the generalizability of current findings is limited by small sample sizes, inconsistent dosing regimens, and underrepresentation of diverse populations (e.g., various ethnic groups and pediatric cohorts). Large-scale, well-designed clinical trials are needed to validate its efficacy, optimize dosing, and assess long-term safety compared to standard therapies.