Current medicinal chemistry · 2026
The NF-κB Inhibitor Pyrrolidinedithiocarbamate Ammonium (PDTC) Exerts an Anti-Pyroptotic Effect in Monocytes.
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Mao Xianxian, Wang Yihan, Lin Hongru, He Xueke, Huang Xiang, Bai Xinyan, Zhan Yixiong, Liu Kai, Yang Min, Wu Yijia, Qian Yisong, Zhang Xiangcheng
Аннотация
OBJECTIVES: Pyroptosis is a type of inflammatory programmed cell death that is triggered by inflammasomes. Pyroptosis exacerbates inflammatory responses and promotes the progression of various inflammation-related diseases, yet effective intervention strategies remain inadequately defined. This study aimed to screen small-molecule inhibitors for their anti-pyroptotic activity in monocytes and clarify the mechanism of the most potent candidate.
MATERIALS AND METHODS: Human monocytic leukemia THP-1 cells were used as the in vitro model via stimulation with 1 μg/mL lipopolysaccharide (LPS) for 3 hours, followed by 8 μg/mL nigericin for 1 hour. Fourteen small molecules were initially screened. Cell viability was assessed via a CCK-8 assay, and pyroptosis-related cytotoxicity was evaluated by measuring lactate dehydrogenase (LDH) release. Calcein AM/PI staining was performed to visualize live/dead cells and observe pyroptotic morphological changes. Western blotting was used to detect the expression and activation of key proteins in the canonical pyroptosis pathway and the Nuclear Factor-κB (NF-κB) signaling pathway. RNA isolation and quantitative PCR (qPCR) were conducted to analyze NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) mRNA expression. Additionally, proteasomal inhibitors (MG132) and autophagy/lysosomal inhibitors were used to explore the mechanism of NLRP3 protein regulation.
RESULTS: The NF-κB inhibitor pyrrolidinedithiocarbamate ammonium (PDTC) exerted a remarkable anti-pyroptotic effect (p < 0.05), as evidenced by reduced LDH release and improved cell viability following LPS + nigericin challenge. PDTC suppressed activation of the canonical pyroptosis pathway by downregulating NLRP3, consequently reducing downstream caspase-1 and Gasdermin D (GSDMD) cleavage, as well as interleukin-1β (IL-1β) secretion (p < 0.01). Mechanistically, PDTC suppressed activation of the NF-κB signaling pathway and dual-regulated NLRP3 expression by inducing proteasomal degradation and suppressing transcription (p < 0.05).
DISCUSSION: Pyroptosis drives uncontrolled inflammation, and pharmacological inhibition of it is a potential strategy for inflammatory diseases. Non-NF-κB inhibitors failed to protect THP-1 cells from pyroptosis. PDTC's dual regulation of NLRP3 goes beyond NF-κB suppression, with its optimal NF-κB inhibitory and anti-pyroptotic concentrations not fully overlapping.
CONCLUSION: These findings suggest that PDTC is a potent inhibitor of pyroptosis in monocytes, exerting effects by suppressing the NF-κB pathway and regulating NLRP3 at transcriptional and post-transcriptional levels, representing therapeutic potential for inflammatory disorders.
MATERIALS AND METHODS: Human monocytic leukemia THP-1 cells were used as the in vitro model via stimulation with 1 μg/mL lipopolysaccharide (LPS) for 3 hours, followed by 8 μg/mL nigericin for 1 hour. Fourteen small molecules were initially screened. Cell viability was assessed via a CCK-8 assay, and pyroptosis-related cytotoxicity was evaluated by measuring lactate dehydrogenase (LDH) release. Calcein AM/PI staining was performed to visualize live/dead cells and observe pyroptotic morphological changes. Western blotting was used to detect the expression and activation of key proteins in the canonical pyroptosis pathway and the Nuclear Factor-κB (NF-κB) signaling pathway. RNA isolation and quantitative PCR (qPCR) were conducted to analyze NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) mRNA expression. Additionally, proteasomal inhibitors (MG132) and autophagy/lysosomal inhibitors were used to explore the mechanism of NLRP3 protein regulation.
RESULTS: The NF-κB inhibitor pyrrolidinedithiocarbamate ammonium (PDTC) exerted a remarkable anti-pyroptotic effect (p < 0.05), as evidenced by reduced LDH release and improved cell viability following LPS + nigericin challenge. PDTC suppressed activation of the canonical pyroptosis pathway by downregulating NLRP3, consequently reducing downstream caspase-1 and Gasdermin D (GSDMD) cleavage, as well as interleukin-1β (IL-1β) secretion (p < 0.01). Mechanistically, PDTC suppressed activation of the NF-κB signaling pathway and dual-regulated NLRP3 expression by inducing proteasomal degradation and suppressing transcription (p < 0.05).
DISCUSSION: Pyroptosis drives uncontrolled inflammation, and pharmacological inhibition of it is a potential strategy for inflammatory diseases. Non-NF-κB inhibitors failed to protect THP-1 cells from pyroptosis. PDTC's dual regulation of NLRP3 goes beyond NF-κB suppression, with its optimal NF-κB inhibitory and anti-pyroptotic concentrations not fully overlapping.
CONCLUSION: These findings suggest that PDTC is a potent inhibitor of pyroptosis in monocytes, exerting effects by suppressing the NF-κB pathway and regulating NLRP3 at transcriptional and post-transcriptional levels, representing therapeutic potential for inflammatory disorders.