ArticleFrontiers in pharmacology2021
Samotolisib Attenuates Acute Liver Injury Through Inhibiting Caspase-11-Mediated Pyroptosis Via Regulating E3 Ubiquitin Ligase Nedd4.
Article in Frontiers in pharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 31 citations in OpenAlex.
- HECT ubiquitin ligases as regulators of inflammatory signalling.Cell death and differentiation · 2026Review
- Gasdermin D-driven pyroptosis in sepsis: mechanisms, therapeutic strategies, and clinical translation.Frontiers in immunology · 2026Review
- Regulated cell death in sepsis-associated liver injury: molecular mechanisms and therapeutic implications.Frontiers in immunology · 2026Review
- Exocarpium Citri Grandis Attenuates Lipopolysaccharide-Induced Acute Liver Injury Through Suppression of Inflammatory, Apoptotic, Oxidative, and Ferroptotic Pathways.Food science & nutrition · 2025Article
- Esketamine mitigates endotoxin-induced acute lung injury by suppressing caspase-11-driven pyroptosis.BMC anesthesiology · 2025Article
- Dimethyl fumarate attenuates liver injury in a mouse model of cecal ligation and puncture by modulating inflammatory, angiogenic and pyroptotic pathways.BMC pharmacology & toxicology · 2025Article
- Review
- Polyphenols alleviate metabolic disorders: the role of ubiquitin-proteasome system.Frontiers in nutrition · 2024Review
- Regulation of PI3K signaling in cancer metabolism and PI3K-targeting therapy.Translational breast cancer research : a journal focusing on translational research in breast cancer · 2024Review
- NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis.International journal of biological sciences · 2024Article
- Regulation of ubiquitination in sepsis: from PAMP versus DAMP to peripheral inflammation and cell death.Frontiers in immunology · 2024Review
- Targeting VEGF using Bevacizumab attenuates sepsis-induced liver injury in a mouse model of cecal ligation and puncture.Journal of medicine and life · 2023Article
- LncRNA 220: A Novel Long Non-Coding RNA Regulates Autophagy and Apoptosis in Kupffer Cells via the miR-5101/PI3K/AKT/mTOR Axis in LPS-Induced Endotoxemic Liver Injury in Mice.International journal of molecular sciences · 2023Article
- NEDD4 ameliorates myocardial reperfusion injury by preventing macrophages pyroptosis.Cell communication and signaling : CCS · 2023Article
- Engineered exosomes enriched in netrin-1 modRNA promote axonal growth in spinal cord injury by attenuating inflammation and pyroptosis.Biomaterials research · 2023Article
- Gasdermins in sepsis.Frontiers in immunology · 2023Review
- Regulatory Roles of Caspase-11 Non-Canonical Inflammasome in Inflammatory Liver Diseases.International journal of molecular sciences · 2022Review
- The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI.Frontiers in medicine · 2021Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Acute liver injury (ALI) is associated with poor survival in patients with sepsis. During sepsis, the liver is the main site of bacterial endotoxin-induced inflammation. Lipopolysaccharide (LPS) promotes caspase-4/5/11 activation, leading to pyroptosis, a major sepsis driver. This study aimed to identify novel drugs that can control hepatocyte caspase-4/5/11 activation during sepsis. We performed LPS-induced caspase-11 activation and pyroptosis in RAW 264.7 cells and established an LPS-induced ALI mouse model. We identified samotolisib (ST), a novel dual phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, by screening a library of 441 pyroptosis compounds with known targets, which dose-dependently inhibited caspase-11 activation and N-terminal fragment of gasdermin D (GSDMD-NT) generation, reducing RAW 264.7 cell pyroptosis. In mice, ST preconditioning improved survival, attenuated LPS-induced serum alanine aminotransferase and aspartate aminotransferase activity, and inhibited severe liver inflammation and damage. Importantly, ST treatment activated Nedd4, which directly interacts with and mediates caspase-11 ubiquitination and degradation. This was largely abrogated by insulin-like growth factor 1. ST ameliorated LPS-induced hepatotoxicity by inhibiting caspase-11/GSDMD-NT pyroptosis signaling via regulating PI3K/AKT/mTOR/Nedd4 signaling. Hence, ST may play a key role in the prevention of liver injury in patients with sepsis.
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