Comprehensive Insights into Biological Roles of Rosmarinic Acid: Implications in Diabetes, Cancer and Neurodegenerative Diseases

Rosmarinic acid (RA), a polyphenolic secondary metabolite first isolated in 1958 from Rosmarinus officinalis, is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid. RA occurs widely in Lamiaceae and other plant families and exhibits antioxidant, anti-inflammatory, antimutagenic, antibacterial, antiviral, and antiallergic activities. Given growing interest in phytochemicals as adjunct therapies, this review examines RA’s therapeutic roles in diabetes, cancer, and neurodegenerative diseases, focusing on reported mechanisms such as inhibition of NF-κB, COX-2, and proinflammatory cytokines, modulation of oxidative stress, and effects on cell proliferation, apoptosis, and metastasis.

- General pharmacology: RA demonstrates anti-inflammatory and antioxidant actions across models by inhibiting NF-κB activation and reducing PGE2, NO, and COX-2 in RAW 264.7 cells. It suppresses TNF-α-mediated ROS generation, apoptosis, and NF-κB activation in U937 leukemia cells and downregulates proinflammatory/protumor mediators (ICAM-1, VCAM-1, PGE2, LTB4, COX-2) in vivo. - Diabetes: RA improves hyperglycemia and insulin resistance in STZ- and high-fat diet-induced rodent models by decreasing hepatic PEPCK and increasing GLUT4 in muscle (dose-dependent). RA exhibits α-glucosidase inhibitory activity. In diabetic nephropathy models (HG-stimulated HK-2 cells; diabetic rats), RA suppresses CTGF, improves renal function, and increases body weight. It reduces oxidative stress and inflammation, producing antihyperalgesic and antiallodynic effects in diabetic neuropathy. RA protects aortic endothelium, restoring vascular function, and prevents brain oxidative damage by inhibiting lipid peroxidation and AChE elevation in diabetic rats. - Neurodegeneration: RA protects neuronal cells against H2O2-induced cytotoxicity (N2A, SH-SY5Y), preserves mitochondrial membrane potential, reduces intracellular ROS, downregulates Bax, upregulates Bcl-2, and induces HO-1. In AD models, RA mitigates Aβ25–35-induced memory impairment via antioxidant and peroxynitrite scavenging effects; in ischemic diabetic stroke models, 50 mg/kg RA reduced HMGB1, histopathological damage, edema, apoptosis, and blocked TNF-α-induced NF-κB in SH-SY5Y cells. In epilepsy models, RA inhibits GABA-T at 100 μg/mL and reduces seizure-induced oxidative damage (decreased ROS, DNA damage; improved SOD activity). In a 3-nitropropionic acid rat HD model, intranasal RA-loaded solid lipid nanoparticles improved behavior and reduced oxidative stress. In 6-OHDA PD rats, RA prevented striatal dopamine depletion, preserved TH-positive neurons, and restored Bcl-2/Bax ratio. - Cancer (selected data): RA inhibits proliferation, induces cell-cycle arrest and apoptosis, and suppresses EMT and metastasis across multiple cancers. • Acute lymphoblastic leukemia: CCRF-CEM and CEM/ADR5000 cells, 48 h IC50 14.6 μM and 44.5 μM; effects include IKK-β inhibition, NF-κB blockade, MMP disruption, caspase-independent death, adhesion loss. • Breast cancer: MDA-MB-231 and MDA-MB-468 IC50 ~321.75 and 340.45 μM (48 h); RA induces apoptosis and cell-cycle arrest (G0/G1 in MDA-MB-231; S-phase in MDA-MB-468). RA inhibits MARK4 and reduces viability of TNBC cells; inhibits bone-homing metastasis in MDA-MB-231BO cells. • Colorectal cancer: HCT8 (IC50 298.1 μM), HCT116 (319.8 μM), Ls174-T (576.3 μM), Lovo (539.4 μM). RA activates AMPK to suppress EMT (↑E-cadherin; ↓N-cadherin, Snail, Twist, Vimentin, Slug), invasion/migration, and MMP-2/9. In mice with CT26 cells, oral RA 100 mg/kg/day for 14 days reduced metastasis and induced cell-cycle arrest; RA suppresses NF-κB/STAT3 in colitis-associated colon cancer and reduces COX-2. • Lung cancer (NSCLC): Rosemary extract inhibits H1299 proliferation (IC50 19 μg/mL) with increased cleaved PARP. RA reduces P-gp and reverses cisplatin resistance via JNK phosphorylation; in A549 and A549DDP cells, RA reduces proliferation (max effect ~14.05 μg/mL in A549; 46.47 μg/mL in A549DDP), induces G1 arrest (↑p53, p21), enhances DDP-induced apoptosis (↑caspase-3, Bax; ↓Bcl-2), and inhibits xenograft growth when combined with DDP. • Prostate cancer: RA inhibits HDAC2 leading to p53-mediated G1 arrest and apoptosis; rosemary extract inhibits proliferation/survival/migration via Akt/mTOR pathway suppression. • Gastric cancer: RA reduces MMP-9, modulates TIMP-1 (protein down; mRNA up), increases collagen I/COL1A1 mRNA, decreases Tn/T antigens and sialylated forms, and lowers MUC1 protein. RA analogue-11 induces apoptosis via EGFR/Akt/NF-κB modulation. Combined RA and anti-MUC1 enhances Gal-3 inhibition, increases Bax/Bad, and suppresses Bcl-2 mRNA. In MKN45 cells/mice, RA counters Warburg effect via IL-6/STAT3 and reduces tumor features. • Cervical cancer: Rosmarinic acid methyl ester inhibits mTOR/S6K1 interaction/signaling, inducing autophagy and apoptosis; co-treatment with cisplatin reduces survival in resistant cells. • Hepatocellular carcinoma: RA (SMMC-7721 cells; mice) inhibits PI3K/AKT/mTOR, EMT, inflammation (↓IL-1β, IL-6, TNF-α), angiogenesis (↓VEGF, TGF-β), and p65 phosphorylation; in HepG2, RA modulates pro-/anti-apoptotic gene expression (↑caspase-8; ↓BCL-2). Overall, RA consistently exhibits anti-inflammatory, antioxidant, anti-EMT, anti-metastatic, pro-apoptotic, and chemosensitizing effects across disease models, supported by in vitro IC50s and in vivo efficacies/doses.

This narrative review synthesizes evidence that rosmarinic acid exerts multimodal biological effects relevant to major chronic diseases. By attenuating oxidative stress and inflammatory signaling (e.g., NF-κB, COX-2, proinflammatory cytokines), modulating metabolic and apoptotic pathways (e.g., AMPK activation, PI3K/AKT/mTOR inhibition, Bcl-2/Bax balance), and influencing glucose and lipid metabolism (↓PEPCK, ↑GLUT4; α-glucosidase inhibition), RA may address key pathogenic mechanisms in diabetes and its complications, neurodegeneration, and cancer. In oncology, RA suppresses proliferation, induces cell-cycle arrest/apoptosis, reverses EMT and metastasis, and sensitizes tumors to chemotherapeutics such as cisplatin. In neurology, RA protects neurons from oxidative and apoptotic injury and improves behavioral and pathological endpoints in models of AD, PD, epilepsy, ischemia, and HD. In diabetes, RA improves glycemic control, vascular/end-organ function, and neuropathic symptoms. Collectively, these findings support RA as a promising dietary component and candidate adjuvant therapeutic, with relevance to pharmacology, biochemistry, and translational medicine.

The review consolidates current knowledge on rosmarinic acid’s therapeutic potential in diabetes, cancer, and neurodegenerative diseases. RA acts through antioxidant and anti-inflammatory mechanisms, inhibition of cell proliferation and migration, selective induction of cancer cell apoptosis, and modulation of key signaling pathways (e.g., NF-κB, STAT3, PI3K/AKT/mTOR, AMPK). Evidence also supports benefits in diabetic complications and neuroprotection. RA and its derivatives hold promise as dietary or adjuvant interventions and as scaffolds for drug development. Future work should optimize bioavailability and delivery systems, develop more potent/selective derivatives, and evaluate clinical efficacy in well-designed trials.

The review highlights limited bioaccessibility and bioavailability of RA due to interactions with food components, gastrointestinal conditions, and first-pass metabolism in the liver and intestines. Absorption challenges may constrain therapeutic translation. There is also a lack of standardized dosing and limited clinical data, indicating a need for improved delivery strategies and further in vivo/clinical investigations.