Stimulator of interferon genes (STING) is an intracellular signaling molecule that senses cytosolic DNA to regulate the production of type I interferons (IFNs) and other inflammatory cytokines. C-176 is a covalent STING inhibitor that effectively decreases STING-mediated IFNβ reporter activity at the dosage of 0.01 – 1.25 μM. Treatment of [3H]-palmitate labelled HEK293T cells with 1 μM C-176 inhibited STING palmitoylation. In wild-type C57BL/6J mice, pretreatment with 750 nmol C-176 for 1h and 4h resulted in a significant reduction of STING agonist-induced IFNs and IL-6 production in serum. Two-week injection of Trex1 deficient mice with C-176 (7.5 μL/day) significantly decreased serum levels of type I IFNs and suppressed cardiac inflammatory parameters. Treatment with C-176 in Trex1-/- mice for three months attenuated systemic inflammatory signs in smooth muscle, tongue and stomach[1].
作用机制
C-176 is a nitrofuran derivative that acts as a STING inhibitor by covalently binding to the Cys91 of mouse STING[1].
C-176 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HK-2 cells
3 μM
48 h
Inhibited STING signaling pathway, alleviated hypoxia-induced fibrosis and inflammatory responses
Cell Death Discov. 2024 Jul 7;10(1):314.
dTHP-1 cells
1 μM
1 h
Pretreatment with C-176 significantly decreased the mRNA expression of IFN-β and IL-1β and slightly reduced the phosphorylation of NF-κB p65. Additionally, C-176 pretreatment suppressed the cleavage of caspase-1 and GSDMD, indicating that the STING signaling pathway is not involved in noncanonical inflammasome activation during HAdV infection.
Front Immunol. 2023 Apr 18;14:1169968.
MPC5 mouse podocytes
1 µM
C176 ameliorated palmitic acid (PA)-induced podocyte injury, as evidenced by restored protein levels of nephrin and podocin, reduced apoptosis, decreased phosphorylation of TBK1 and NF-κB p65, and reduced levels of IL-6 and TNF-α.
iScience. 2022 Sep 16;25(10):105145.
H446 cells
1 μM
48 h
To detect the expression levels of STING pathway-related proteins. The results showed that the protein expression levels of p-IRF3 and p-STING decreased after treatment with C-176
Cell Death Discov. 2023 Aug 5;9(1):289.
H1688 cells
1 μM
48 h
To detect the expression levels of STING pathway-related proteins. The results showed that the protein expression levels of p-IRF3 and p-STING decreased after treatment with C-176
Cell Death Discov. 2023 Aug 5;9(1):289.
BV2 cells
0.5 μM
1 h
To investigate the anti-inflammatory effects and mechanisms of C-176 in an in vitro SAH model, results showed that C-176 significantly decreased the expression of M1 microglial markers and upregulated AMPK phosphorylation.
J Neuroinflammation. 2020 May 25;17(1):165.
C-176 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Oxidative stress-induced retina degeneration model
Intraperitoneal injection
10 mg/kg
Once daily for 3 days
C176 inhibited SI-induced cGAS-STING activation and reduced retina destruction and subretinal immune cell infiltration.
Cell Death Differ. 2022 Sep;29(9):1816-1833
Mice
Unilateral ureteral obstruction (UUO) model
Intraperitoneal injection
750 nM/mouse
Once daily for 14 days
Inhibited STING signaling pathway, alleviated UUO-induced renal fibrosis and inflammation
Cell Death Discov. 2024 Jul 7;10(1):314.
Mice
LLC lung metastasis model
Intraperitoneal injection
13.4 mg/kg
Once daily for 24 days
STING inhibition significantly reversed the STING-activated DC maturation and migration in Tfam-/- mice and promoted tumor progression and metastasis
J Immunother Cancer. 2023 Mar;11(3):e005430
Mice
Subcutaneous xenograft model
Intraperitoneal injection
5 mg/kg
Once daily for 7 days
To evaluate the effect of C-176 on the GPR162-STING signaling pathway induced by radiotherapy, results showed that C-176 significantly reduced the anti-tumor effect of radiotherapy
Signal Transduct Target Ther. 2023 Feb 1;8(1):48
Mice
CKD/ApoE−/− mice
Intraperitoneal injection
4 mg/kg
Every other day for 12 weeks
Significantly retarded AS progression and improved plaque vulnerability
Adv Sci (Weinh). 2021 Jan 6;8(5):2002738.
Mice
Db/db mice
Intraperitoneal injection
5 mg/kg
Once daily for 21 consecutive days
C176 inhibited the cGAS-STING pathway and ameliorated podocyte injury in db/db mice, as evidenced by reduced microalbuminuria, alleviated glomerular hypertrophy and mesangial expansion, restored nephrin levels, and reduced podocyte apoptosis.
iScience. 2022 Sep 16;25(10):105145.
C57BL/6J mice
Subarachnoid hemorrhage (SAH) model
Intraperitoneal injection
750 nM, 200 μL
Single dose, 30 minutes post-modeling
To investigate the neuroprotective effects and mechanisms of C-176 in an SAH model, results showed that C-176 significantly attenuated brain edema, neuronal injury, and improved both short-term and persistent neurological dysfunction, with its anti-inflammatory effects partially mediated by AMPK signaling.
搜索
