3,4-Dihydroxybenzoic acid (Protocatechuic acid) is a natural polyphenolic compound found in many edible and medicinal plants[1]. 3,4-Dihydroxybenzoic acid exhibits significant antioxidant activity[2], neuroprotective effects[3], and anticancer properties[4].
In vitro, treatment of human HepG2 hepatocellular carcinoma cells with 3,4-Dihydroxybenzoic acid (100μM) for 4 days induced cell death through a mechanism dependent on c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK)[5]. Treatment of human glioma cell lines U87 and U251 with 3,4-Dihydroxybenzoic acid (2.5–10μM) for 24–48 hours significantly inhibited cell proliferation, invasion, and migration, and induced pyroptosis via a mechanism dependent on the NLRP3/caspase-1/GSDMD signaling axis[6].
In vivo, dietary supplementation with 3,4-Dihydroxybenzoic acid (0.025–0.1%w/w) for 12 weeks in high-fat diet-fed C57BL/6J mice significantly ameliorated metabolic-associated fatty liver disease (MAFLD) by inhibiting the growth of Enterococcus faecalis in the gut and modulating insulin signaling pathways[7]. Intramuscular administration of 3,4-Dihydroxybenzoic acid (100mg/kg/day) for 9 days in an isoproterenol (80mg/kg/day)-induced heart failure model using C57BL/6 mice significantly improved cardiac function and attenuated cardiac hypertrophy and fibrosis[8].
References:
[1] Khan AK, Rashid R, Fatima N, et al. PHARMACOLOGICAL ACTIVITIES OF PROTOCATECHUIC ACID. Acta Pol Pharm. 2015 Jul-Aug;72(4):643-50.
[2] Zhang X, Luo J, Bharati L, Hua Z, et al. Protocatechuic acid suppresses ferroptosis to protect against hypoxic-ischemic encephalopathy by targeting the HIF-1α/VEGFA axis. Phytomedicine. 2025 Jul 25;143:156900.
[3] Krzysztoforska K, Mirowska-Guzel D, Widy-Tyszkiewicz E. Pharmacological effects of protocatechuic acid and its therapeutic potential in neurodegenerative diseases: Review on the basis of in vitro and in vivo studies in rodents and humans. Nutr Neurosci. 2019 Feb;22(2):72-82.
[4] Cadena-Iñiguez J, Santiago-Osorio E, Sánchez-Flores N, et al. The Cancer-Protective Potential of Protocatechuic Acid: A Narrative Review. Molecules. 2024 Mar 23;29(7):1439.
[5] Yip EC, Chan AS, Pang H, et al. Protocatechuic acid induces cell death in HepG2 hepatocellular carcinoma cells through a c-Jun N-terminal kinase-dependent mechanism. Cell Biol Toxicol. 2006 Jul;22(4):293-302.
[6] Zhang W, Cai Y, Zheng H. Protective Role of Protocatechuic Acid in Glioma: Modulation of Cell Growth, Migration, and Pyroptosis via NLRP3/Caspase-1/GSDMD Axis. Discov Med. 2025 Apr;37(195):659-668.
[7] Tan J, Hu R, Gong J, et al. Protection against Metabolic Associated Fatty Liver Disease by Protocatechuic Acid. Gut Microbes. 2023 Jan-Dec;15(1):2238959.
[8] Bai L, Han X, Kee HJ, et al. Protocatechuic acid prevents isoproterenol-induced heart failure in mice by downregulating kynurenine-3-monooxygenase. J Cell Mol Med. 2023 Aug;27(16):2290-2307.