Related Experiment Video

Updated: Jul 4, 2025

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

10.9K

Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL

Jingyi Li1, Xingfeng Liu1, Yuanyuan Liu1

  • 1The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.

Cell Death & Disease
|February 8, 2024
PubMed

Insights

Saracatinib effectively inhibits necroptosis, a form of programmed cell death, by targeting the MLKL protein. This discovery offers a promising therapeutic strategy for inflammatory skin conditions like psoriasis.

Area of Science:

  • Cellular Biology
  • Immunology
  • Pharmacology

Background:

  • Necroptosis, a programmed cell death pathway, releases inflammatory signals contributing to diseases like skin inflammation.
  • Tumor necrosis factor α (TNF)-induced necroptosis is characterized by the activation of RIPK1, RIPK3, and MLKL.
  • Current therapeutic strategies for necroptosis-related inflammation are limited.

Purpose of the Study:

  • To identify small molecules that inhibit TNF-induced necroptosis.
  • To elucidate the mechanism by which identified compounds exert their inhibitory effects.
  • To evaluate the therapeutic potential of these compounds in preclinical models of skin inflammation.

Main Methods:

  • Screening of a small-molecule compound library to identify inhibitors of TNF-induced necroptosis.
  • Biochemical assays to assess the effect of compounds on MLKL phosphorylation, translocation, and oligomerization.
  • In vivo studies using an imiquimod (IMQ)-induced psoriasis mouse model to evaluate therapeutic efficacy.

Main Results:

  • Saracatinib was identified as a potent inhibitor of TNF-induced necroptosis.
  • Saracatinib targets MLKL, preventing its phosphorylation, translocation, and oligomerization.
  • In a mouse model of psoriasis, saracatinib effectively reduced MLKL phosphorylation and inflammatory responses.

Conclusions:

  • Saracatinib inhibits necroptosis by directly targeting MLKL.
  • The findings suggest saracatinib as a potential therapeutic agent for necroptosis-driven inflammatory diseases, including psoriasis.
  • Targeting MLKL represents a viable strategy for managing skin inflammation.

More Related Videos

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway07:15

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway

Published on: August 23, 2024

416
Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells09:15

Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells

Published on: October 20, 2022

2.2K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.6K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
8.9K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.5K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.5K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K