Cited by 1,397Immune cells in cancerCancer, Hypoxia, and MetabolismImmune Response and Inflammation

The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index; none of the 26 sources its claims cite is checked for support yet.

Pyruvate Kinase M2 Regulates Hif-1α Activity and IL-1β Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages

Open access

Palsson-McDermott, Eva M., Curtis, Anne M., Goel, Gautam, Lauterbach, Mario A.R., Sheedy, Frederick J., Gleeson, Laura E., van den Bosch, Mirjam W.M., Quinn, Susan R., Domingo-Fernandez, Raquel, Johnston, Daniel G.W., Jiang, Jian-kang, Israelsen, William J., Keane, Joseph, Thomas, Craig, Clish, Clary, Vander Heiden, Matthew, Xavier, Ramnik J., O’Neill, Luke A.J.·2015·Cell Metabolism

DOI 10.1016/j.cmet.2014.12.005PMC PMC5198835

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Abstract

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.

AI snapshot

Written from the paper’s full text.

TL;DR

LPS induces PKM2 in macrophages, where dimeric/monomeric PKM2 complexes with Hif-1α and binds the IL-1β promoter to promote Warburg-like glycolysis and pro-inflammatory activation. Forcing PKM2 into tetramers with DASA-58 or TEPP-46 inhibits Hif-1α activity, IL-1β induction, glycolytic reprogramming, and succinate accumulation, while shifting macrophages toward an M2-like/IL-10-high phenotype and impairing bacterial killing in vivo.

Key findings

LPS induced PKM2 expression and tyrosine 105 phosphorylation in BMDMs; Pkm2 mRNA increased approximately 2.8-fold after 24 hours, and phospho-PKM2 showed a 10.3-fold increase in relative band intensity, consistent with inactive monomer/dimer formation.
PKM2 activators DASA-58 and TEPP-46 promoted tetramerization, inhibited LPS-induced nuclear translocation of PKM2, and blocked LPS-induced Hif-1α protein, pro-IL-1β, Il1b mRNA, and the Hif-1α target Ldha, without affecting IL-6 or TNF.
LPS increased PKM2–Hif-1α association and binding of both to the IL-1β promoter; TEPP-46/DASA-58 inhibited this binding. PKM2 deletion reduced LPS-induced Hif-1α, Il1β, and Ldha, and reduced glycolysis, while increasing oxidative phosphorylation.
DASA-58 blocked LPS-induced succinate and glycolytic intermediates; LPS caused up to a ten-fold increase in glycolysis that was markedly inhibited by TEPP-46 and DASA-58. In vivo, TEPP-46 reduced LPS- and Salmonella typhimurium-induced IL-1β, boosted IL-10, and increased bacterial dissemination.

Methods

Primary BMDMs and peritoneal cells from C57BL/6 mice, RAW 264.7 macrophages, and conditional PKM2fl/fl BMDMs were treated with LPS, TEPP-46, DASA-58, tamoxifen, Mtb, or S. typhimurium.
Main assays included Western blotting, DSS crosslinking, size-exclusion chromatography, nuclear/cytosolic fractionation, ELISA, qPCR, co-immunoprecipitation, oligonucleotide pulldown, sequential ChIP, Seahorse extracellular flux analysis, microarray profiling, and LC-MS metabolomics.
In vivo models used LPS-induced sepsis and S. typhimurium infection in mice treated with TEPP-46 or vehicle, measuring serum cytokines, peritoneal cell IL-1β, and bacterial CFU in liver/spleen.

Limitations

The paper does not include a dedicated limitations section.
Limitations evident from the text: most mechanistic work uses mouse BMDMs/PECs and RAW cells; in vivo infection experiments use TEPP-46 only because DASA-58 is not pharmacokinetically validated in vivo; some data are not shown; and the mechanism by which PKM2 promotes IL-10 production is stated to require further analysis.
The Mtb ELISA results are described as means ± SEMs for one representative experiment with n=2, limiting statistical robustness.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2014.12.005

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 26 cited sources checked · 0 supported · 0 flagged

A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Disuccinimidyl suberate (DSS) crosslinking of lysates from LPS treated BMDMs suggest that LPS induced PKM2 is primarily of a monomeric configuration (Figure 1B).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · boosted
  “This is further supported by results from the cross-linking experiments shown in Figure 1B, where DSS cross-linked lysates from LPS treated BMDMs failed to reveal any high molecular weight PKM2 complexes.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Load-bearingStrength:boosted· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, there is an increased binding of both PKM2 and Hif-1α to this promoter site in response to LPS (compare lane 2 to lane 1).”
- Also stated in: § LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter · plain
  “As seen in Figure 3C, LPS causes increased binding of endogenous Hif-1α to the IL-1β promoter (left panel), and interestingly after this sample was put through a second round of ChIP specific for PKM2 (right panel) we also see an increased binding of endogenous PKM2 to the same copy of DNA in response to LPS.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes

Show all 74 claims

It may state two separate claims as one. 51
Probably not a substantial claim. 9
The quote only partly states this claim. 1

A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
  “LPS induced high levels of PKM2 in BMDMs up to 48 hours (Figure 1A).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · boosted
  “LPS strongly induced Pkm2 mRNA expression (Figure 1C), with expression levels increasing approximately 2.8 fold after 24 hours of LPS.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LPS- induced expression of PKM2 causes concurrent phosphorylation of Tyrosine 105 to an extent comparable or greater to the increased expression levels.”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
  “This phosphorylation is evident after just one hour, with the strongest induction after 48 hours (Figure 1A middle panel, 10.3 fold increase in relative band intensity).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“however as expected Pkm1 expression was compensatorily increased (Figure 5B).”
- Also stated in: § Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages · plain
  “whereas PKM1 protein was upregulated following Tamoxifen and LPS-treatment compared to control (Figure 5C second panel).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“However, although as expected LPS causes a reduction on OCR in PKM2+/+ cells (Tannahill et al., 2013), the same inhibitory effect was still observed in BMDMs derived from PKM2−/− cells (data not shown).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages
What the sources say
- Not checked yetcites Tannahill et al., 2013 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“We confirmed that LPS stimulation leads to accumulation of upstream glycolytic intermediates, such as G6P, FBP, DHAP and 2-PG, and TCA cycle intermediates including succinate (Tannahill et al., 2013).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Tannahill et al., 2013 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This impairs the ability of the PKM2 and Hif-1α complex to bind to the Hif-1α motif in the promoter of the known Hif-1α target gene IL-1β (Peyssonnaux et al., 2007; Zhang et al., 2006), thereby inhibiting the transcriptional activity of Hif-1α and induction of IL-1β”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Peyssonnaux et al., 2007 source
- Not checked yetcites Zhang et al., 2006 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“In order to examine the functional relevance of PKM2 for LPS action we next examined the effect of two highly specific small-molecule PKM2 activators, TEPP-46 and DASA-58.”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
  “They promote the formation of active PKM2 tetramers thereby boosting PKM2 enzymatic activity and limiting tumor growth in vivo (Anastasiou et al., 2012).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“Phosphorylation of PKM2 on Tyrosine 105 is indicative of monomer/dimer formation, as it prevents PKM2 tetramer configuration, further promoting the Warburg effect (Hitosugi et al., 2009).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
What the sources say
- Not checked yetcites Hitosugi et al., 2009 source
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“PKM2 has been shown to interact with Hif-1α and stimulate Hif-1α transactivation domain function and recruitment of p300 to the Hif Response Element (HRE) of Hif-1α target genes (Luo et al., 2011).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter
What the sources say
- Not checked yetcites Luo et al., 2011 source
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.”
- Also stated in: § INTRODUCTION · boosted
  “This event is required for macrophage activation by LPS and we identify PKM2 as a critical modulator of IL-1β production, macrophage polarization, glycolytic reprogramming and Warburg metabolism in LPS-activated macrophages.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Current data indicates that PKM2, when highly expressed, exists in an equilibrium of enzymatically inactive pyruvate kinase dimers (or monomers) which can translocate into the nucleus(Christofk et al., 2008; Hitosugi et al., 2009), and enzymatically active tetramers which are retained in the cytosol(Mazurek et al., 2005).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Christofk et al., 2008 source
- Not checked yetcites Hitosugi et al., 2009 source
- Not checked yetcites Mazurek et al., 2005 source
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The pyruvate kinase activity of the tetramers can be regulated by the concentration of the naturally occurring upstream glycolytic intermediate FBP (Ashizawa et al., 1991; Jurica et al., 1998), serine (Chaneton et al., 2012), as well as by a multitude of post-translational modifications (Wu and Le, 2013) including tyrosine phosphorylation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Ashizawa et al., 1991 source
- Not checked yetcites Jurica et al., 1998 source
- Not checked yetcites Chaneton et al., 2012 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As the main causative agent of tuberculosis, Mtb signals mainly through TLR 2, 6 and 9 (Bafica et al., 2005; Means et al., 1999).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
What the sources say
- Not checked yetcites Bafica et al., 2005 source
- Not checked yetcites Means et al., 1999 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“TEPP-46, but not DASA-58, is pharmacokinetically validated in vivo (Anastasiou et al., 2012).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 results in increased bacterial dissemination in a Salmonella typhimurium model of infection
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“This event has been shown to be important for the Warburg effect in hypoxia and cancer(Hitosugi et al., 2009).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Hitosugi et al., 2009 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Activation of PKM2 also limits this response and this will lead to Hif-1α destabilization.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Hif-1α is stabilized by succinate inhibiting PHDs.
In the paper
“These well-characterized and highly specific compounds bind PKM2, which then forms a tight tetramer with PKM1-like kinetic properties, an event that is resistant to inhibition by tyrosine phosphorylation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“This could explain the increase in IL-10 production, which in the case of M2 macrophage activity may require mitochondrial oxidative metabolism (Krawczyk et al., 2010).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Krawczyk et al., 2010 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Secondly, the decrease in succinate will further limit Hif-1α through stabilization and degradation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one. The quote only partly states this claim.
- Rests on an assumption: Hif-1α is stabilized by succinate inhibiting PHDs.

57 of 57

The paper relies on this without support.
There is only limited information on the precise molecular determinants of the profound metabolic change in LPS-activated macrophages.
“There is only limited information on the precise molecular determinants of this profound change in metabolism.”
The paper relies on this without support.
LPS-activated macrophages have a high demand for biosynthetic precursors and increased energy demand, and these events are required for the cells to respond to infection or tissue injury during inflammation.
“In macrophages activated with the TLR4 agonist LPS there is a high demand for biosynthetic precursors including proteins, lipids, and nucleic acids as well as increased energy demand. These events are required for the cells to respond to infection or tissue injury during inflammation.”
The paper relies on this without support.
PKM2 enters the nucleus as a dimer.
“Since previous reports have established that PKM2 enters the nucleus as a dimer, we then carried out further DSS cross-linking studies in order to support a model for nuclear exclusion of PKM2 following treatment with our small molecule activators.”
The paper relies on this without support.
Hif-1α is stabilized by succinate inhibiting PHDs.
“Hif-1α will also be stabilized by succinate inhibiting PHDs, providing further regulation of Hif-1α.”
The paper relies on this without support.
Mycobacterium tuberculosis utilizes TLR2, TLR6 and TLR9.
“This extended our observation beyond TLR4 and LPS to a bacterial pathogen that utilizes TLR2, TLR6 and TLR9.”

5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Chromatography treatment is named TEPP-58 instead of TEPP-46
Minor
The methods name TEPP-58 for the size-exclusion experiment, while the results identify TEPP-46 as the treatment in that experiment.

1 of 1

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Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation
Yang, W., Xia, Y., Ji, H., Zheng, Y., Liang, J., Huang, W., Gao, X., Aldape, K., & Lu, Z. (2011) · Nature · doi:10.1038/nature10598 · Cited by 1,051 · cited 2×
“Other nuclear functions of dimeric PKM2 includes the ability to act as a protein kinase, activating transcription of mek5 through phosphorylation of STAT3(Gao et al., 2012) as well as promoting β-catenin translocation, leading to expression of cyclinD1 and c-myc(Yang et al., 2011).”

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Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti‐Neuroinflammatory Agents for Ischemic Stroke
Gao, C., Hou, G., Liu, J., Ru, T., Xu, Y., Zhao, S., Ye, H., Zhang, L., Chen, K., Guo, Y., et al. (2019) · Angewandte Chemie · doi:10.1002/ange.201912489 · Cited by 11
Shanzhiside methyl ester attenuated cognitive impairment in diabetic mice by inhibiting neuroinflammation and glycolysis via HSP90AA1/HIF1A/STAT1
Chen, T., Ai, L., Shuang, R., Diao, J., Yuan, X., Tao, W., He, L., & Chen, C. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157103 · Cited by 10
Sirt5-mediated polarization and metabolic reprogramming of macrophage sustain brain function following ischemic stroke
Zhang, L., Lv, T., Hou, P.-P., Jin, Y., & Jia, F. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149613 · Cited by 12
Tissue-Resident Macrophages in Cardiovascular Diseases: Heterogeneity and Therapeutic Potential
An, T., Guo, M., Wang, Z., & Liu, K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104524 · Cited by 11
Metabolic evolutionary roots of the macrophage immune response in amoeba-bacteria interactions: The conserved role of hypoxia-induced Factor and AMP kinase
Dzik, J. (2021) · Acta Biochimica Polonica · doi:10.18388/abp.2020_5683 · Cited by 10
Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes
Vrieling, F., van Dierendonck, X. A. M. H., Jaeger, M., Janssen, A. W. M., Hijmans, A., Netea, M. G., Tack, C. J., & Stienstra, R. (2022) · Immunometabolism · doi:10.1097/in9.0000000000000008 · Cited by 10
“This is in line with the well-established increase in the glycolytic rate of immune cells upon activation [5], which supports functional changes in the cells, including cytokine release [18,42].”
Background
Inhibition of hexokinase 2 with 3-BrPA promotes MDSCs differentiation and immunosuppressive function
Shi, Z.-Y., Yang, C., Lu, L., Lin, C.-X., Liang, S., Li, G., Zhou, H., & Zheng, J. (2023) · Cellular Immunology · doi:10.1016/j.cellimm.2023.104688 · Cited by 10
Bacterial Lipoproteins Shift Cellular Metabolism to Glycolysis in Macrophages Causing Bone Erosion
Nguyen, M.-T., Hu, Z., Mohammad, M., Schöttler, H., Niemann, S., Schultz, M., Barczyk-Kahlert, K., Jin, T., Hayen, H., & Herrmann, M. (2023) · Microbiology spectrum · doi:10.1128/spectrum.04293-22 · Cited by 11
Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections
Lane, S., White, T. L. A., Walsh, E., Cattley, R. T., Cumberland, R. L., Hawse, W. F., Delgoffe, G. M., Badylak, S. F., & Bomberger, J. M. (2023) · mBio · doi:10.1128/mbio.00863-23 · Cited by 10
“To determine whether activation of PKM2 is sufficient for impaired clearance of S. aureus , we pretreated macrophages with TEPP-46, a PKM2 activator (39, 41), and performed an antibiotic protection assay.”
BackgroundMethodResultInfluential
Unraveling the complex roles of macrophages in obese adipose tissue: an overview
Peng, C. S., Chen, J., Wu, R., Jiang, H., & Li, J. X. (2024) · Frontiers of Medicine · doi:10.1007/s11684-023-1033-7 · Cited by 9
Immunometabolic Signatures of Circulating Monocytes in Humans With Obesity and Insulin Resistance
Smeehuijzen, L., Gijbels, A., Nugteren‐Boogaard, J. P., Vrieling, F., Boudjadja, M. B., Trouwborst, I., Jardon, K. M. C., Hul, G. B. J., Feskens, E. J. M., Blaak, E. E., et al. (2024) · Diabetes · doi:10.2337/db23-0970 · Cited by 10
Cost of surviving sepsis: a novel model of recovery from sepsis in Drosophila melanogaster
Kaynar, A. M., Bakalov, V., Laverde, S. M., Cambriel, A. I. F., Lee, B.-H., Towheed, A., Gregory, A. D., Webb, S. A. R., Palladino, M. J., Bozza, F. A., et al. (2016) · Intensive Care Medicine Experimental · doi:10.1186/s40635-016-0075-4 · Cited by 10
β-Ionone-Derived Curcumin Analogs as Potent Anti-Inflammatory Agents
Hu, W.-L., Cai, M., Qi, D.-S., Ying, X., Huang, C., & Xing, C.-G. (2018) · Pharmaceutical Chemistry Journal · doi:10.1007/s11094-018-1713-9 · Cited by 11
Selenoproteome Identification in Inflamed Murine Primary Bone Marrow-Derived Macrophages by Nano-LC Orbitrap Fusion Tribrid Mass Spectrometry
Korwar, A. M., Shay, A. E., Basrur, V., Conlon, K. P., & Prabhu, K. S. (2019) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-019-02192-9 · Cited by 10
“Prototypical inflammatory markers such as Il1b, Nos2, Tlr4, Stat1, and Icam1 were upregulated in these cells indicating that our cell culture system, treatments, and proteomic analysis were in close agreement with that reported in the literature (Figure 4a) [36].”
Sweet regulation – The emerging immunoregulatory roles of hexoses
Xu, J., Zhao, Y., Mertens, R. T., Ding, Y., & Xiao, P. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.04.014 · Cited by 9
“Besides acting as a metabolic enzyme, PKM2 directly forms a complex with HIF-1 a to activate the transcription of the IL-1 b -encoding gene (Il1b) [175].”
Treponema Pallidum protein Tp47 triggers macrophage inflammatory senescence via PKM2-mediated metabolic reprogramming
Xie, J., Guo, Y., Fan, S.-H., Zheng, Y., Zhang, H., Zhang, Y., Zhang, Y., & Lin, L. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.137991 · Cited by 9
Targeting mTOR in myeloid cells prevents infection-associated inflammation
Toner, Y. C., Munitz, J., Prévot, G., Morlà‐Folch, J., Wang, W., van Elsas, Y., Priem, B., Deckers, J., Anbergen, T., Beldman, T. J., et al. (2025) · iScience · doi:10.1016/j.isci.2025.112163 · Cited by 9
“23 Moreover, mTOR prompts hypoxia-inducible factor 1-alpha (HIF-1 a ) expression, which in turn promotes the release of IL-1 b 24,25 and upregulates the expression of glycolytic enzymes and glucose transporters, increasing glucose inﬂux and usage by immune cells.”
Dexmedetomidine alleviates sepsis-induced acute lung injury by inhibiting M1 macrophage polarization via inhibition of PKM2-mediated Warburg effect
He, Y., Xie, W., Zhou, H., Wang, Y., Chen, L., Xu, Z., Feng, Y., Liu, G., Liu, J., Li, X., et al. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117130 · Cited by 9
Macrophage plasticity and glucose metabolism: the role of immunometabolism in pulmonary arterial hypertension
Jefferson, L., Lima, P., & Archer, S. L. (2025) · Clinical Science · doi:10.1042/cs20257363 · Cited by 10
“In LPS-stimulated inflammatory macrophages, the expression of PKM2 is elevated, while its activity is reduced compared with unstimulated or IL-4-stimulated anti-inflammatory macrophages [110,111], suggesting a preference for glycolysis in inflammatory macrophages.”
Role of macrophage PKM2 in inflammation and tumor progression and its targeted therapy
Li, Y., Zhu, L., Liu, L., & Li, B. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189478 · Cited by 9
Single-cell multiomics reveals macrophage-derived IL-23 and CXCL9/10 drive pathogenic IFNG + IL17 + T cells in immunotherapy-related colitis
Tang, Z., Shi, J., Xu, S., Liu, S., Yin, W., Xiang, Y., Li, J., He, Z., Yao, X., Zhou, L., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-011959 · Cited by 10
Covalent targeting GAPDH by Pudilan formula and baicalein suppresses macrophage Warburg effect to alleviate acute lung injury
Jiang, M., Yang, Y., Zhang, Y., Zhang, P., Zhang, Q., Yang, T., Zhang, G., Zhou, J., Chu, Z., Li, S., et al. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157727 · Cited by 9
Molecular Mechanisms Underlying Atherosclerosis and Current Advances in Targeted Therapeutics
Zhu, B. J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020634 · Cited by 11
Attenuating Effect of Chlorella Extract on NLRP3 Inflammasome Activation by Mitochondrial Reactive Oxygen Species
Nakashima, Y., Gotoh, K., Mizuguchi, S., Setoyama, D., Takata, Y., Kanno, T., & Kang, D. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.763492 · Cited by 10
The Immunomodulatory Role of Hypoxic Tumor-Derived Extracellular Vesicles
Beaumont, J. E. J., Beelen, N. A., Wieten, L., & Rouschop, K. M. A. (2022) · Cancers · doi:10.3390/cancers14164001 · Cited by 9
Is TGR5 a therapeutic target for the treatment of spinal cord injury?
Smaling, A., Romero‐Ramírez, L., & Mey, J. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15727 · Cited by 9
Blood transcriptome reveals immune and metabolic-related genes involved in growth of pasteurized colostrum-fed calves
Li, C., Li, S., Yang, C., Ding, Y., Zhang, Y., Wang, X., Zhou, X., Su, Z., Ming, W., Zeng, L., et al. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1075950 · Cited by 9
Myeloid differentiation factor-2/LY96, a potential predictive biomarker of metastasis and poor outcomes in prostate cancer: clinical implications as a potential therapeutic target
Ferrari, M. G., Jiménez‐Uribe, A. P., Wang, L., Hoeppner, L. H., Murugan, P. J., Hahm, E., Yu, J., Kuzel, T. M., Gradilone, S. A., & Mansini, A. P. (2023) · Oncogene · doi:10.1038/s41388-023-02925-x · Cited by 9
Tetrameric PKM2 Activation Curbs CD4+ T Cell Overactivation
Jiang, S. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.04.001 · Cited by 10
Label-free two-photon imaging of mitochondrial activity in murine macrophages stimulated with bacterial and viral ligands
Allen, C. H., Ahmed, D., Raiche-Tanner, O., Chauhan, V., Mostaço-Guidolin, L. B., Cassol, E., & Murugkar, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-93043-9 · Cited by 9
HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow–Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability
Ahmed, D., Humphrey, A., Roy, D., Sheridan, M.-E., Versey, Z., Jaworski, A. F., Edwards, A., Donner, J., Abizaid, A. B., Willmore, W. G., et al. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2001282 · Cited by 9
Renoprotection of Microcystin-RR in Unilateral Ureteral Obstruction-Induced Renal Fibrosis: Targeting the PKM2-HIF-1α Pathway
Ren, Y., Wang, J., Guo, W., Chen, J., Wu, X., Gu, S., Xu, L., Wu, Z., & Wang, Y. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.830312 · Cited by 9
Macrophage heterogeneity in liver fibrosis
Wang, W., Li, S., Liu, Y., Ding, X., Yang, Y., Chen, S., Cao, J., Tacke, F., Dong, W., & Lan, T. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1639455 · Cited by 8
Intestinal microflora promotes Th2-mediated immunity through NLRP3 in damp and heat environments
Luo, Y., Huang, X., Hu, H., Wang, Y., Feng, X., Chen, S., & Luo, H. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1367053 · Cited by 8
Engineering antigen-presenting cells for immunotherapy of autoimmunity
Smith, C. T., Wang, Z., & Lewis, J. S. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115329 · Cited by 9
Intrathecal Fumagillin Alleviates Chronic Neuropathy-Induced Nociceptive Sensitization and Modulates Spinal Astrocyte-Neuronal Glycolytic and Angiogenic Proteins
Wen, Z., Wu, Z., Cheng, H., Huang, S., Tang, S.-H., Teng, W.-N., Su, F.-W., Chen, N., & Sung, C.-S. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04254-w · Cited by 12
“Moreover, the relationship between PKM2 and HIF-1α is a positive feedback loop that can upregulate the expression of the proinflammatory cytokine interleukin-1β [98].”
Highly expressed VGLL3 in keloid fibroblasts promotes glycolysis and collagen production via the activation of Wnt/β-catenin signaling
Liu, Y., Yang, Z., Lin, N., Liu, Y., & Chen, H. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.111604 · Cited by 8
Sulfur dioxide controls M1 macrophage polarization by sulphenylation of prolyl hydroxylase 2 at cysteine 260
Zhang, H., Lv, B., Liu, K., Du, J., Jin, H., & Huang, Y. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.01.054 · Cited by 9
The mechanisms and effects of lactylation modification in different kinds of cancers
Sun, Y., Yang, X., Kong, F., Dong, F. Y., Li, N., & Wang, S. (2025) · Discover Oncology · doi:10.1007/s12672-025-02359-9 · Cited by 8
Liposome-encapsulated AICAR hydrogel regulates macrophage metabolic reprogramming via SIK1 activation to alleviate osteoarthritis
Fu, Y., Hou, J., Yang, Q., Lin, Y., Rui, N., Wang, J., Wu, H., & Yu, B. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03543-3 · Cited by 8
Metabolism and Targeted Therapy of Fibrosis in Chronic Pancreatitis: A Review
Luo, H., Guo, S., Chu, Y., Xin, Y., Yin, X., & Li, X. (2025) · International Journal of Medical Sciences · doi:10.7150/ijms.118338 · Cited by 10
Regulation of osteogenic differentiation in vascular smooth muscle cells under high-glucose condition
Guo, J., & Du, L. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1589160 · Cited by 11
Scutellarin suppresses Mycobacterium tuberculosis-induced pyroptosis in macrophages by inhibiting the HIF-1α-mediated Warburg effect
Wu, J., Liu, F., Shen, J., Zhang, H., Liu, Y., Sun, J., Yang, G., Zheng, Y., & Jiang, X. (2025) · Redox Report · doi:10.1080/13510002.2025.2565861 · Cited by 8
“Metabolic reprogramming in macrophages is primarily driven by HIF-1α, which upregulates the expression of glycolytic enzymes and pro-inflammatory cytokines (such as IL-1β) while inhibiting OXPHOS activity[37].”
Targeting Metabolic Reprogramming in Tumor: From Mechanisms to Precision Immunotherapies
Zhang, T., Gao, P., & Sun, L. (2025) · MedComm – Oncology · doi:10.1002/mog2.70045 · Cited by 10
Senescence-associated metabolic alterations aggravate calcific aortic valve disease
Qian, X., Xu, L., Zheng, Y., Fan, Z., Jiang, C., Liu, Y., Tong, F., Fan, P., Chen, M., Chen, Z., et al. (2026) · European Heart Journal · doi:10.1093/eurheartj/ehag191 · Cited by 8
Hypoxia signalling in the regulation of innate immune training
Eades, L., Drozd, M., & Cubbon, R. M. (2021) · Biochemical Society Transactions · doi:10.1042/bst20210857 · Cited by 9
Innate sensing and cellular metabolism: role in fine tuning antiviral immune responses
Ahmed, D., Daraawi, M. A., & Cassol, E. (2023) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiac011 · Cited by 8
Pyruvate kinase M2 modification by a lipid peroxidation byproduct acrolein contributes to kidney fibrosis
Kuo, C.-W., Chen, D., Tsai, M., Lin, C., Cheng, H.-W., Tsay, Y., & Wang, H. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1151359 · Cited by 8
“While PKM2 activation promotes the synthesis of tetrameric PKM2 and decreases lipopolysaccharide (LPS)-induced HIF-1α accumulation (17), the PKM2 dimer interacts directly with HIF-1α, increasing HIF-1α transactivation leading to the production of its downstream glycolytic genes (18, 19).”
Background
Systems Biology
Konieczny, L., Roterman-Konieczna, I., & Spólnik, P. (2023) · Springer eBooks · doi:10.1007/978-3-031-31557-2 · Cited by 11
Novel insights into macrophage immunometabolism in nonalcoholic steatohepatitis
Yuan, Y., Zhang, Y., Lu, X., Li, J., Wang, M., Zhang, W., Zheng, M., Sun, Z., Xing, Y., Li, Y., et al. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.111833 · Cited by 8
Roles of Critical Amino Acids Metabolism in The Interactions Between Intracellular Bacterial Infection and Macrophage Function
Zhang, Z., Wang, Y., Xia, L., & Zhang, Y. (2024) · Current Microbiology · doi:10.1007/s00284-024-03801-x · Cited by 10
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis
de Mattos, S. E. C., Diel, L. F., Bittencourt, L. D. S., Schnorr, C. E., Gonçalves, F. A., Bernardi, L., & Lamers, M. L. (2021) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x202010504 · Cited by 8
“, succinate, that stabilize hypoxiainducible factor-1a (HIF-1a) driving IL-1b and IL-6 production (53).”
Background
Detection of Nail Oncometabolite SAICAR in Oral Cancer Patients and Its Molecular Interactions with PKM2 Enzyme
Patel, R., Kumar, A., Lokhande, K. B., Almasri, M., Alzahrani, K. J., Almeslet, A., Swamy, K. V., Sarode, G. S., Sarode, S. C., Patil, S., et al. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph182111225 · Cited by 8
“This prediction is well supported by the existing literature on the role of SAICAR and PKM2 activation is associated with the pro-inflammatory act by macrophages that may work as cancer-supporting non-cancer cells [41,42].”
Background
Evaluation of serum antioxidative status, immune status and intestinal condition of Linwu duck challenged by lipopolysaccharide with various dosages and replications
Liu, Y., Jiang, G., Huang, X., Li, C., Huang, X., Zhang, X., Lin, Q., Liu, S., & Dai, Q. (2021) · Poultry Science · doi:10.1016/j.psj.2021.101199 · Cited by 8
Metabolic reprogramming of macrophages instigates CCL21‐induced arthritis
Raemdonck, K. V., Umar, S., Palasiewicz, K., Meyer, A., Volin, M. V., Chang, H. J., Al‐Awqati, M., Zomorrodi, R. K., & Shahrara, S. (2021) · Immunology and Cell Biology · doi:10.1111/imcb.12512 · Cited by 8
Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2
Zhao, S., Sun, Y., Wu, X., Yang, Y., Fan, K., Hu, K., Qin, Y., Li, K., Lin, L., Chen, K., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1092943 · Cited by 8
Overexpression of CXCL14 Alleviates Ventilator-Induced Lung Injury through the Downregulation of PKM2-Mediated Cytokine Production
Zhu, R., Lei, Y.-Q., & Zhao, D.-C. (2020) · Mediators of Inflammation · doi:10.1155/2020/7650978 · Cited by 8
“It has been reported that PKM2 could promote interleukin-1beta (IL-1β) release in lipopolysaccharide- (LPS-) stimulated macrophages [8].”
Targeting macrophage polarization for therapy of diabesity–the feasibility of early improvement of insulin sensitivity and insulin resistance-a comprehensive systematic review
Kaur, K. K., Allahbadia, G. N., & Singh, M. (2021) · Journal of Diabetes Metabolic Disorders & Control · doi:10.15406/jdmdc.2021.08.00216 · Cited by 8
Pyruvate dehydrogenase kinase inhibitor dichloroacetate augments autophagy mediated constraining the replication of Mycobacteroides massiliense in macrophages
Quan, H., Chung, H., Je, S., Hong, J. J., Kim, B., Na, Y. R., & Seok, S. H. (2023) · Microbes and Infection · doi:10.1016/j.micinf.2023.105139 · Cited by 7
Clinical efficacy evaluation and potential mechanism prediction on Guizhi-Shaoyao-Zhimu decoction in the treatment of gouty arthritis based on meta-analysis, network pharmacology analysis, and molecular docking
Qu, P., Wang, H., Wang, W., Hu, Q., Du, S., Peng, Z., & Tang, X. (2023) · Medicine · doi:10.1097/md.0000000000035973 · Cited by 9
Deciphering metabolic crosstalk in context: lessons from inflammatory diseases
Verheijen, F. W., Minh, T. T. N., Chang, J., Broere, F., Zaal, E. A., & Berkers, C. R. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13588 · Cited by 8
Search progress of pyruvate kinase M2 (PKM2) in organ fibrosis
Lv, S., Cao, M., Luo, J., Fu, K., & Yuan, W. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09307-w · Cited by 8
“Activation of PKM2 can diminish the pro-inflammatory M1 macrophage phenotype induced by lipopolysaccharide (LPS) while enhancing M2 macrophage characteristics [ 62 ].”
High‐intensity interval training improves hypothalamic inflammation by suppressing HIF ‐1α signaling in microglia of male C57BL / 6J mice
Chen, Y., Zhang, S., Ye, L., Chen, H., Ma, P., & Wu, D. (2024) · The FASEB Journal · doi:10.1096/fj.202400289r · Cited by 9
Association between clinical-biological characteristics of Klebsiella pneumoniae and 28-day mortality in patients with bloodstream infection
Yu, X., Zhao, Y., Xiao, S., Luan, J., Wang, H., Sun, T., Lin, T., Zhou, X., Yang, W., Deng, Z., et al. (2024) · BMC Microbiology · doi:10.1186/s12866-024-03714-6 · Cited by 7
Transcription Factor Blimp-1: A Central Regulator of Oxidative Stress and Metabolic Reprogramming in Chronic Inflammatory Diseases
Wang, A. Y. L., Aviña, A. E., Liu, Y., Chang, Y., & Kao, H. (2025) · Antioxidants · doi:10.3390/antiox14020183 · Cited by 7
HIF-1α Promotes Inflammatory Responses in Aspergillus Fumigatus Keratitis by Activating Pyroptosis Through Caspase-8/GSDMD Pathway
Yang, H., Liu, M., Song, S., Xu, Q., Lee, J., Sun, J., Xue, S., Sun, X., & Che, C. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.6.32 · Cited by 7
“Similarly, Eva et al. 39 demonstrated that inhibiting HIF-1 α mitigated the LPS-induced pro-inflammatory M1 macrophage phenotype while promoting characteristics typical of the M2 macrophage phenotype.”
Glycolytic reprogramming in macrophage polarization: New horizons in the treatment of tumor diseases
Wang, D., & Guan, H. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.111940 · Cited by 8
USP32 promotes temporomandibular joint osteoarthritis by modulating PKM2 stability and glycolytic metabolism in chondrocytes
Zhao, J., Li, R.-J., Du, T., Wang, M., Li, M., Feng, Z., Liu, Z., & Qi, K. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-08053-6 · Cited by 8
F13A1‐Mediated Macrophage Activation Promotes MASH Progression via the PKM2/HIF1A Pathway
Lu, Q., Ong, M., Yi, X., Xing, M., Tian, X., Zhang, K., Lu, L., Wang, H., Lin, X., Fang, J., et al. (2025) · Advanced Science · doi:10.1002/advs.202518128 · Cited by 10
Self-citation
Mycobacterium tuberculosis manipulates LINC02528 in macrophages to modulate anti-tuberculosis metabolic immunity
Xu, Y., Zhang, K., Li, S., Qiao, L., Mo, S., Wang, W., Zhu, J., Liu, X., Cai, N., Shi, C., et al. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1013810 · Cited by 7
Lactylation modification - a bridge between sepsis and macrophage metabolic reprogramming
Fang, Z., Zhu, G. S., Nie, D. Y., & Xu, B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1738765 · Cited by 7
Inflammasome Targeted Therapy as Novel Treatment Option for Aortic Aneurysms and Dissections: A Systematic Review of the Preclinical Evidence
Wortmann, M., Klotz, R., Kalkum, E., Dihlmann, S., Böckler, D., & Peters, A. S. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.805150 · Cited by 7
“Pharmaceutical activation of PKM2 by its selective activator TEPP-46 supresses NLRP-3 mediated IL-1β secretion (38, 39).”
Background
Intracellular pyruvate levels positively correlate with cytokine production capacity in tolerant monocytes from patients with pneumonia
Otto, N. A., Butler, J. M., Schuurman, A. R., Brands, X., Haak, B. W., Klarenbeek, A. M., van Weeghel, M., Houtkooper, R. H., Jakobs, M. E., Faber, D. R., et al. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166519 · Cited by 7
Proinflammatory Polarization of Macrophages Causes Intestinal Inflammation in Low-Birth-Weight Piglets and Mice
Zhang, X., Wu, Y., Liu, X., Lin, X., Liu, Y., Kang, L., Ye, H., Wang, Z., Ma, Y., Dai, Z., et al. (2023) · Journal of Nutrition · doi:10.1016/j.tjnut.2023.04.016 · Cited by 8
Treponema pallidum recombinant protein Tp47 activates NOD-like receptor family protein 3 inflammasomes in macrophages via glycolysis
Zheng, X., Li, Z., Meng, Q.-Q., Li, W. S., Li, Q., Xie, L., Xiao, Y., Xu, Q., & Chen, Y.-Y. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.111204 · Cited by 7
Differential impact of high-salt levels in vitro and in vivo on macrophage core functions
Müller, L., Nasr, A. R., Jux, B., Makdissi, N., Trowbridge, J. W., Schmidt, S. V., Schultze, J. L., Quast, T., Schulte-Schrepping, J., Kolanus, W., et al. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09295-x · Cited by 8
TIPE1 limits virus replication by disrupting PKM2/ HIF-1α/ glycolysis feedback loop
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Authors: Palsson-McDermott, E. M., Curtis, A. M., Goel, G., Lauterbach, M. A. R., Sheedy, F. J., Gleeson, L. E., van den Bosch, M. W. M., Quinn, S. R., Domingo-Fernandez, R., Johnston, D. G. W., Jiang, J.-K., Israelsen, W. J., Keane, J., Thomas, C., Clish, C., Vander Heiden, M., Xavier, R. J., & O’Neill, L. A. J.
Affiliations: Broad Institute (US)
Trinity College Dublin (IE)
National Institutes of Health (US)
Koch Institute for Integrative Cancer Research At MIT (US)
ORCID: Goel, Gautam
Lauterbach, Mario A.R.
Sheedy, Frederick J.
Gleeson, Laura E.
Quinn, Susan R.
Johnston, Daniel G.W.
Jiang, Jian-kang
Israelsen, William J.
Keane, Joseph
Thomas, Craig
Clish, Clary
Xavier, Ramnik J.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2015-01
Volume: 21
Issue: 1
Pages: 65-80
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2014.12.005
PMC: PMC5198835
OpenAlex: W2153586956
Cited by: 1,397
References: 38
Citations by year: 2026: 154 · 2025: 177 · 2024: 186 · 2023: 133 · 2022: 132 · 2021: 161 · 2020: 140 · 2019: 81 · 2018: 85 · 2017: 77 · 2016: 51 · 2015: 19
FWCI: 38.04
Type: journal article
Language: en
Update notices: erratum (2015-02-03)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Funders: Health Research Board
Seventh Framework Programme (FP7-2007-2013, HEALTH-14-2011-281608)
National Institutes of Health
European Research Council
Science Foundation Ireland
Wellcome Trust
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: PKM2, HIF-1α, IL-1β, Warburg effect, macrophage polarization, M1/M2 macrophages, lipopolysaccharide stimulation, TLR4, glycolytic reprogramming, succinic acid, TEPP-46, IL-10, Salmonella typhimurium, inflammation, macrophage metabolism
MeSH terms: Animals, Bone Marrow Cells, Cells, Cultured, Glycolysis, Lipopolysaccharides, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Promoter Regions, Genetic, Protein Binding, Pyruvate Kinase, RNA, Messenger, Salmonella typhimurium, Gene Expression, Enzyme Activators, Toll-Like Receptor 4, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Interleukin-1beta

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Pyruvate Kinase M2 Regulates Hif-1α Activity and IL-1β Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages

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