**Background**
The NLRP3 inflammasome plays a pivotal role in the innate immune response, where its activation leads to the maturation and release of pro-inflammatory cytokines such as IL-1β and IL-18. Dysregulation of the NLRP3 pathway is implicated in various inflammatory conditions, including sepsis, peritonitis, and acute lung injury, as well as the progression of certain malignancies. Consequently, targeting the NLRP3 inflammasome has become a significant strategy for developing therapeutic interventions for these diseases. In the context of oncology, inhibiting inflammatory signaling and inducing apoptosis are critical for treating hepatocellular carcinoma. Therefore, we will introduce a selective, orally active NLRP3 inhibitor – Tabersonine.
**Definition**
Tabersonine is an indole alkaloid that acts as a selective NLRP3 inhibitor, demonstrating an IC50 of 0.71 μM for inhibiting NLRP3-mediated IL-1β production in BMDM cells.
**Mechanism of Action**
According to the Tabersonine description, this compound directly binds to the NACHT domain of NLRP3, which inhibits its ATPase activity and oligomerization. This mechanism blocks the formation of ASC spots and the activation of caspase-1, thereby reducing the release of IL-1β. Furthermore, Tabersonine inhibits the K63-linked ubiquitination of TRAF6, which subsequently blocks the NF-κB, PI3K/Akt, and p38 MAPK signaling pathways. In the context of Tabersonine Cancer research, the compound induces apoptosis in liver cancer cells via mitochondrial and death receptor pathways by reducing mitochondrial membrane potential and promoting cytochrome c release.
**In Vitro and In Vivo Studies**
Extensive Tabersonine in vitro studies have demonstrated its potent biological activity. In human liver cancer cells (SMMC-7721, HepG2), Tabersonine (0.78-25 μM; 24 h) inhibited cell viability, with a stronger effect on tumor cells than on normal HL-7702 cells. Specifically, in SMMC-7721 cells, Tabersonine (6.25-25 μM; 24 h) induced apoptosis by upregulating Bax, cleaved-caspase-3, and cleaved-PARP while downregulating Bcl-2. Additionally, concentrations of 12.5-25 μM arrested the cell cycle at the G0/G1 phase via downregulation of CDK4 and Cyclin D1.
Tabersonine in vivo data further support its therapeutic potential. In mouse models of LPS-induced acute lung injury, Tabersonine (10-40 mg/kg; i.p.; daily for 30 days) reduced lung tissue damage, neutrophil infiltration, and levels of TNF-α, IL-6, and IL-1β. In a nude mouse HepG2 liver cancer xenograft model, oral administration of Tabersonine (25, 50 mg/kg; daily for 3 weeks) significantly inhibited tumor growth and promoted apoptosis. Moreover, in E. coli-induced sepsis models, Tabersonine (10 mg/kg; gavage; 3 times daily) increased the 48-hour survival rate to 60%. In conclusion, Tabersonine is a potent NLRP3 inhibitor with significant potential for treating inflammatory diseases and liver cancer.
Keywords
Tabersonine, 4429-63-4, Akt, Interleukin Related, NF-κB, p38 MAPK, CDK, NOD-like Receptor (NLR), Caspase, Apoptosis, Cytochrome P450, PI3K, PKB, Protein kinase B, IL
References
[1] Zhang D, et al. Tabersonine attenuates lipopolysaccharide-induced acute lung injury via suppressing TRAF6 ubiquitination. Biochem Pharmacol. 2018 Aug;154:183-192.
[2] Li X, et al. Tabersonine Induces the Apoptosis of Human Hepatocellular Carcinoma In vitro and In vivo. Anticancer Agents Med Chem. 2024;24(10):764-772.
[3] Xu HW, et al. Tabersonine, a natural NLRP3 inhibitor, suppresses inflammasome activation in macrophages and attenuate NLRP3-driven diseases in mice. Acta Pharmacol Sin. 2023 Jun;44(6):1252-1261.