Caffeic acid is a hydroxycinnamic acid polyphenol compound with antioxidant activity. Caffeic acid is an inhibitor of TRPV1 ion channel and 5-lipoxygenase. Caffeic acid scavenges free radicals and chelates metal ions. Caffeic acid inhibits inflammatory signaling pathways such as NF-κB and activates Nrf2 pathway to enhance cellular antioxidant defense. These actions reduce oxidative stress and inflammation. Caffeic acid can be used for research on oxidative stress, inflammation, microbial infection, and tumor[1-4].
In vitro, treatment of A2780 cells and cisplatin-resistant A2780cisR cells with 50µM Caffeic acid and 5-20µM Cisplatin for 24-48 hours enhanced cisplatin cytotoxicity, increased nuclear DNA platinum binding, and activated Caspase-3[5]. Treatment of HT-29 cells with 1.68μg/ml Caffeic acid for 24 hours downregulated CTSZ, AFF4, DHRS2, and HMGCS1 gene expression and upregulated HINT3, SIAE, and DHRS2 gene expression[6]. Treatment of MDA-MB-231 and MDA-MB-468 cells with 100-300µM Caffeic acid for 48 hours inhibited cell proliferation, induced apoptosis, arrested cell cycle at G2/M phase, decreased mitochondrial membrane potential, reduced reactive oxygen species levels, downregulated FOXO1 protein, upregulated phosphorylated FOXO1, upregulated mitochondrial fission proteins FIS and DRP1, decreased CD44-positive tumor stem cell sphere proportion, reduced sphere volume, activated lysosomes, and induced mitophagy[7].
In vivo, oral gavage of 50mg/kg/day Caffeic acid to Aβ1–42-induced mice for 2 weeks improved spatial learning, memory, and cognitive ability, decreased reactive oxygen species and lipid peroxidation levels in the brain, downregulated Aβ and BACE-1 expression, and enhanced PI3K/AKT, BDNF, and synaptic marker SNAP-25, Synaptophysin, SNAP-23, and PSD-95 expression[8]. Intraperitoneal injection of 20mg/kg Caffeic acid into ApoE-/- mice every other day for 2 months reduced atherosclerotic lesion area in the aorta and aortic sinus, alleviated cognitive decline, and decreased hippocampal β-amyloid accumulation[9]. Daily oral gavage of 10mg/kg Caffeic acid to pulmonary fibrosis BALB/c mouse models for 3 weeks prolonged treadmill exercise time, decreased serum TNF-α, IL-6, and IL-1β concentrations, attenuated pulmonary septal thickening, and reduced pulmonary tissue collagen deposition[10].
References:
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[2] Calabrese EJ, Pressman P, Hayes AW, Baldwin L, Agathokleous E, Dhawan G, Kapoor R, Calabrese V. Caffeic Acid: Numerous Chemoprotective Effects are Mediated via Hormesis. J Diet Suppl. 2024;21(6):842-867.
[3] Cortez N, Villegas C, Burgos V, et al. Adjuvant Properties of Caffeic Acid in Cancer Treatment. Int J Mol Sci. 2024 Jul 11;25(14):7631.
[4] Almatroodi SA, Rahmani AH. Caffeic Acid and Human Health: Evidence-Based Roles in Disease Prevention and Treatment. Int J Mol Sci. 2026 May 23;27(11):4719.
[5] Sirota R, Gibson D, Kohen R, et al. The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines. Redox Biology. 2017;11:170-175.
[6] Rezaei-Tavirani M, Rezaei Tavirani M, Zamanian Azodi M. The bioinformatics aspects of gene screening of HT-29, human colon cell line treated with caffeic acid. Gastroenterol Hepatol Bed Bench. 2019;12(3):246-253.
[7] Xie C, Chan L, Pang Y, et al. Caffeic acid inhibits the tumorigenicity of triple-negative breast cancer cells through the FOXO1/FIS pathway. Biomedicine & Pharmacotherapy. 2024 Jul;178:117158.
[8] Khan A, Park JS, Kang MH, et al. Caffeic Acid, a Polyphenolic Micronutrient Rescues Mice Brains against Aβ-Induced Neurodegeneration and Memory Impairment. Antioxidants. 2023;12:1284.
[9] Sun R, Wu T, Xing S, et al. Caffeic acid protects against atherosclerotic lesions and cognitive decline in ApoE-/- mice. Journal of Pharmacological Sciences. 2023;151(2):110-118.
[10] Zhu Y, Zhang Y, Zhang Q, et al. Caffeic Acid Acts as a Potent Senomorphic and Alleviates Inflammation and Lung Fibrosis by Covalently Targeting Annexin A5 Protein in Mice. Exploration. 2025;5:20240069.