Trigonelline, an alkaloid isolated from Trigonella foenum-graecum L or Leonurus artemisia, is a potent and specific inhibitor of Nrf2[1]. Nrf2 (nuclear factor erythroid 2–related factor 2) is the master transcriptional regulator of cellular antioxidant defense, eliminating reactive oxygen species and maintaining redox homeostasis by up-regulating genes such as HO-1 and NQO1[2]. Trigonelline is widely used in research related to anti-diabetes, anti-oxidation, anti-inflammation and neuroprotection by blocking NrF2-dependent proteasome activity[3][4].
In vitro, pretreatment of H9c2 cells with Trigonelline (25-125µM; 24h) before H₂O₂ stimulation significantly rescued cell morphology, attenuated H₂O₂-induced cell deaths, enhanced antioxidant activity, down-regulated the expression of apoptotic genes (caspase-3, caspase-9), and up-regulated the expression of anti-apoptotic genes (Bcl-2, Bcl-XL)[5]. Trigonelline (0.1-1mM; 16h) significantly inhibited Nrf2 activity in pancreatic cancer cell lines (Panc1, Colo357, MiaPaca2) and H6c7 pancreatic duct cells, reduced nuclear Nrf2 levels and proteasome activity, and enhanced cell sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and etoposide-induced apoptosis, increasing caspase-3/7 activity by 2.3-4.3 fold[6].
In vivo, Trigonelline (10mg/kg/day; i.p.; 14 days) reversed silica-induced pulmonary fibrosis, reduced the expression of fibrotic markers (such as Collagen 1 and Fibronectin) in lung tissues, inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-β/Smad signaling, and improved fibrotic pathological features in a silica-induced pulmonary fibrosis mouse model[7].
References:
[1] Nguyen V, Taine EG, Meng D, Cui T, Tan W. Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline. Int J Mol Sci. 2024;25(6):3385.
[2] Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018;1865(5):721-733.
[3] Ozçelik B, Kartal M, Orhan I. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharm Biol. 2011;49(4):396-402.
[4] Su Y, Zhao B, Zhou L, et al. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett. 2020;483:127-136.
[5] Ilavenil S, Kim DH, Jeong YI, et al. Trigonelline protects the cardiocyte from hydrogen peroxide induced apoptosis in H9c2 cells. Asian Pac J Trop Med. 2015;8(4):263-268.
[6] Arlt A, Sebens S, Krebs S, et al. Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene. 2013;32(40):4825-4835.
[7] Zhang F, Yue H, Dong R, et al. Trigonelline hydrochloride attenuates silica-induced pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation. Respir Res. 2024;25(1):242.