The noncanonical inflammasome-induced pyroptosis and septic shock

Wu, Junru; Cai, Jingjing; Tang, Yiting; Lu, Ben

doi:10.1016/j.smim.2023.101844

Cited by 7 publications

(5 citation statements)

References 181 publications

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“…Regarding this, the inhibition of CASP1 activation by co-treatment with a CASP4 inhibitor during GGA treatment suggests that activation of the non-canonical pathway may trigger the activation of the canonical pathway. Indeed, recent reviews [36,37] suggesting that the non-canonical pathway's efflux of K + to the extracellular space and increased mitochondrial ROS production serve as triggers for the secondary activation of the canonical pathway support our findings.…”

Section: The Mechanism Of Gga-induced Cell Deathsupporting

confidence: 86%

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Shidoji

2024

Preprint

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Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA's unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA's potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA's anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.

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Section: The Mechanism Of Gga-induced Cell Deathsupporting

confidence: 86%

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Shidoji

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Regarding this, the inhibition of CASP1 activation by cotreatment with a CASP4 inhibitor during GGA treatment suggests that activation of the non-canonical pathway may trigger the activation of the canonical pathway. Indeed, recent reviews [38,39] suggesting that the non-canonical pathway's efflux of K + to the extracellular space and increased mitochondrial ROS production serve as triggers for the secondary activation of the canonical pathway support our findings.…”

Section: The Mechanism Of Gga-induced Cell Deathsupporting

confidence: 86%

Induction of Hepatoma Cell Pyroptosis by Endogenous Lipid Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Shidoji

2024

Cells

View full text Add to dashboard Cite

Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) have emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA’s unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA’s potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA’s anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.

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“…GSDMD is a critical regulator of pro-inflammatory cytokine secretion by immune cells, and recent evidence suggests a pivotal modulatory role for GSDMD in the pathogenesis of sepsis. 241 , 342 Although various sensors and mediators activate pyroptosis, the pore-forming activity of GSDMD-NT emerges as a compelling therapeutic target, as it is a universal terminal step required for pyroptosis and the secretion of pro-inflammatory cytokines in response to pathogenic or danger-induced signals. GSDMD inhibition or inactivation does prevent lethal bacterial sepsis, with GSDMD −/− mice displaying markedly enhanced survival over WT controls in models of sepsis induced by LPS and cecum ligation and puncture (CLP).…”

Section: Gasdermins and Diseasesmentioning

confidence: 99%

The gasdermin family: emerging therapeutic targets in diseases

Zhu,

Xu,

Jiang

et al. 2024

Sig Transduct Target Ther

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The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player in pyroptosis. This recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization, pyroptosis, and the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants and infections. GSDMs have been implicated in a range of diseases including, but not limited to, sepsis, viral infections, and cancer, either through involvement in pyroptosis or independently of this process. The regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various diseases. Current strategies for inhibiting GSDMD primarily involve binding to GSDMD, blocking GSDMD cleavage or inhibiting GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In this review, we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis, elucidate the activation mechanisms of GSDMs, explore their associations with a range of diseases, and discuss recent advancements and potential strategies for developing GSDMD inhibitors.

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The noncanonical inflammasome-induced pyroptosis and septic shock

Cited by 7 publications

References 181 publications

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Induction of Hepatoma Cell Pyroptosis by Endogenous Lipid Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

The gasdermin family: emerging therapeutic targets in diseases

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