The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index; none of the 41 sources its claims cite is checked for support yet.
Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels
Open accessAbstract
Metabolic reprogramming is emerging as a hallmark of the innate immune response, and the dynamic control of metabolites such as succinate serves to facilitate the execution of inflammatory responses in macrophages and other immune cells. Immunoresponsive gene 1 (Irg1) expression is induced by inflammatory stimuli, and its enzyme product cis-aconitate decarboxylase catalyzes the production of itaconate from the tricarboxylic acid cycle. Here we identify an immunometabolic regulatory pathway that links Irg1 and itaconate production to the succinate accumulation that occurs in the context of innate immune responses. Itaconate levels and Irg1 expression correlate strongly with succinate during LPS exposure in macrophages and non-immune cells. We demonstrate that itaconate acts as an endogenous succinate dehydrogenase inhibitor to cause succinate accumulation. Loss of itaconate production in activated macrophages from Irg1(-/-) mice decreases the accumulation of succinate in response to LPS exposure. This metabolic network links the innate immune response and tricarboxylic acid metabolism to function of the electron transport chain.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This paper identifies an immunometabolic pathway in which Irg1/CAD-derived itaconate inhibits succinate dehydrogenase (SDH), causing succinate accumulation during LPS exposure. Loss of Irg1 in macrophages reduces itaconate and succinate, linking innate immune metabolism to TCA cycle and electron transport chain function.
Key findings
- In LPS-activated RAW 264.7 macrophages, itaconate and succinate levels showed similar trends over 6 h, unlike citrate, α-ketoglutarate, fumarate, and malate; basal oxygen consumption rate remained unchanged.
- Exogenous itaconate (0–25 mM, 6 h) increased intracellular itaconate dose-dependently and correlated strongly with succinate in resting and LPS-activated RAW 264.7 macrophages (r = 0.99) and in A549 cells (r = 0.99), while other TCA intermediates correlated poorly or negatively.
- Itaconate was not metabolized to succinate: [1-13C]glutamine labeling produced ~65% M1 itaconate but no succinate labeling, and prelabeling with [U-13C6]glucose/[U-13C5]glutamine left succinate labeling ~90% after unlabeled itaconate.
- Itaconate inhibited SDH/complex II: dose-dependent OCR inhibition in permeabilized RAW 264.7 macrophages and BMDMs with succinate, >75% reduction with 10 mM itaconate plus succinate/rotenone, and no effect on complex I or IV substrates; Irg1 KO BMDMs failed to produce itaconate and had significantly lower succinate than WT after LPS, while Irg1 overexpression in A549 cells increased succinate.
Methods
- Cell models and treatments: RAW 264.7 macrophages, A549 lung adenocarcinoma cells, and primary BMDMs from C57BL/6J and Irg1 KO mice; LPS at 10 ng/ml; itaconate at 5, 10, and 25 mM for 6 h; A549 cells transfected with pCMV6-Irg1 or empty vector.
- Metabolite and isotope analysis: GC-MS quantification of itaconate and TCA intermediates using external standard curves; isotopic labeling with [1-13C]glutamine, [U-13C6]glucose, and [U-13C5]glutamine; mass isotopomer distributions corrected for natural abundance.
- Respiration and statistics: Seahorse XF96 oxygen consumption measurements in intact and permeabilized cells (perfringolysin O) with succinate/rotenone, glutamate/malate, pyruvate/malate, or ascorbate/TMPD/antimycin A; Pearson correlation and two-tailed Student’s t tests.
Limitations
- Stated: The authors note variability in succinate accumulation between RAW 264.7 macrophages and BMDMs, likely due to cell, medium, and LPS variability; they also state that the physiological role of itaconate and Irg1 requires further investigation, particularly in macrophage development and differentiation.
- Stated: It is not known whether downstream inflammatory responses are mediated directly by succinate or itaconate or through other mechanisms; no mammalian mitochondrial or plasma membrane itaconate transporters have been described, and other succinate-producing pathways (GABA shunt, glutaminolysis) could compensate.
- Evident from the text: Most mechanistic experiments use cultured cells and exogenous itaconate up to 25 mM, whereas endogenous macrophage itaconate is cited as up to 8 mM; no in vivo inflammation or disease model is presented.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
29 Own result · 25 Not checked yet · 21 Own interpretation · 1 No basis given
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 observed a dose depen- dent inhibition of OCRs by itaconate in RAW 264.7 macrophages (Fig. 5a) and BMDMs (Fig. 5b)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Itaconate also failed to impact this complex IV-mediated respiration.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Notably, basal oxygen consumption rates (OCR) remained unchanged compared with resting macrophages (Fig. 1b).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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, medium itaconate levels were not appreciably affected (Fig. 2g).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Because labeling of succinate after exposure to exogenous, unlabeled itaconate was unchanged (even in the physi-ological concentration used here) (Fig. 4d)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 observed that intracellular itaconate levels correlated strongly with succinate levels in resting (r ϭ 0.99) as well as LPS-activated macrophages (r ϭ 0.99)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Intriguingly, the levels of itaconate and succinate exhibited similar trends upon activation, in contrast to the dynamics of citrate, ␣-ketoglutarate, fumarate, and malate (Fig. 1a)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“the levels of other TCA intermediates, including citrate, ␣-ketoglutarate, fumarate, and malate correlated poorly (or in some cases negatively) with intracellular itaconate levels (Fig. 2, a, b, d, and f).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Loss of itaconate production in activated macrophages from Irg1 ؊/؊ mice decreases the accumulation of succinate in response to LPS exposure.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“oxygen consumption rates in permeabilized cells in the presence of either pyruvate with malate or glutamate with malate, substrates that drive respiration via complex I activity, were not affected by itaconate supplementation.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 10
- Probably not a substantial claim. 13
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
“Succinate levels increased linearly with itaconate levels and correlated strongly (r ϭ 0.99), whereas other TCA cycle intermediates, including citrate, ␣-ketoglutarate, fumarate, and malate, did not accumulate (Fig. 3a).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Although we observed high fractions of M1 itaconate isotopologues (ϳ65%) because of itaconate production via reductive glutamine metabolism, no labeling was detected on succinate (Fig. 4b).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“exposure to exogenous itaconate induces succinate accumulation in resting RAW 264.7 macrophages (Fig. 2e) as well as resting BMDMs (Fig. 2h)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Within our analyses, we did observe variability in succinate accumulation upon LPS stimulation when comparing RAW 264.7 macrophages and BMDMs.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The first break occurs at isocitrate dehydrogenase, leading to the accumulation of citrate, the precursor for itaconate”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although itaconate has been shown previously to inhibit SDH ex vivo (26 -28)”
What the sources say
- Not checked yetcites [26] Booth, 1952, The inhibitory effects of itaconic acid in vitro and in vivo, J. Biol. Chem. source
- Not checked yetcites [27] Ackermann, 1949, Enzyme inhibition in relation to chemotherapy, Proc. Soc. Exp. Biol. Med. source
- Not checked yetcites [28] Dervartanian, 1964, Studies on succinate dehydrogenase: I: spectral properties of the purified enzyme and formation of enzyme-competitive inhibitor complexes, Biochim. Biophys. Acta.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“although glycolytic metabolism is a prerequisite (14).”
What the sources say
- Not checked yetcites [14] Palsson-McDermott, 2015, Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages, Cell Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“the second break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.”
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“The emerging role of itaconate as a regulatory molecule to reprogram immune cell metabolism provides an intriguing link between innate immunity, metabolism, and disease pathogenesis.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Rests on an assumption: The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
In the paper
“Itaconate was only recently identified as an endogenous mammalian biochemical (19), and subsequent studies demonstrated that this molecule was produced by mammalian CAD activity on cis-aconitate (20).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, in particular those that regulate succinate levels, which, in turn, can influence HIF signaling or other pathways (13,25,40,41).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [13] Mills, 2014, Succinate: a metabolic signal in inflammation, Trends Cell Biol source
- Not checked yetcites [25] Jha, 2015, Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization, Immunity source
- Not checked yetcites [40] Chouchani, 2016, A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury, Cell Metab source
- Not checked yetcites [41] Chouchani, 2014, Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Intracellular signaling pathways also play key roles in macrophage polarization and likely sustain inflammation to some degree in the absence of Irg1 (44).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [44] Sica, 2012, Macrophage plasticity and polarization: in vivo veritas, J. Clin. Invest. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Glutamine serves as a major carbon source for succinate production in LPSactivated macrophages via ␣-ketoglutarate or, alternatively, through the GABA shunt (9).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This variance is in the range of succinate accumulation levels reported by others and is likely a function of cell, medium formulation, and LPS variability (9).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“As such, itaconate may have pleiotropic effects on cells depending on the expression, K i , and compartment-specific impacts on succinate concentrations.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“As noted above, various other pathways (e.g.GABA shunt, glutaminolysis) contribute to succinate synthesis in macrophages and could allow compensation (9, 13, 14).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
- Not checked yetcites [13] Mills, 2014, Succinate: a metabolic signal in inflammation, Trends Cell Biol source
- Not checked yetcites [14] Palsson-McDermott, 2015, Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages, Cell Metab source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Given the regulatory role of itaconate in succinate accumulation described here, IRG1-mediated itaconate production may act as a signaling molecule in other inflammatory situations or cellular states.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. 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
“Taken together, our data highlight a mechanistic function of itaconate whereby this metabolite acts as a SDH inhibitor to influence TCA cycle metabolism by driving succinate accumulation (Fig. 7).”
- Also stated in: § Discussion · plain
“This metabolite contributes to succinate accumulation in macrophages by acting as an endogenous SDH inhibitor.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Loss of Irg1 Influences Succinate Levels in
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Discussion · plain
None of the sources cited for this claim have been checked yet.
In the paper
“Succinate inhibits HIF-1␣ signaling through inhibition of PHD2 but can also impact the activity of numerous ␣-ketoglutarate-dependent dioxygenases (42,43).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [42] Xiao, 2012, Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors, Genes Dev source
- Not checked yetcites [43] Metallo, 2013, Understanding metabolic regulation and its influence on cell physiology, Mol. Cell. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
The specific driver(s) of succinate accumulation in inflammatory macrophages have not yet been identified.
“However, the specific driver(s) of this phenomenon has/have not yet been identified.”
The paper relies on this without support.
A potential role of endogenously produced itaconate in succinate accumulation under inflammatory conditions has not yet been addressed and is unknown.
“a potential role of endogenously produced itaconate in succinate accumulation under inflammatory conditions has not yet been addressed and is unknown.”
The paper relies on this without support.
The Irg1 KO mouse model specifically abolishes itaconate production without other metabolic adaptations that affect succinate levels.
“Notably, succinate concentrations in stimulated BMDMs from Irg1 KO mice were significantly lower than those quantified in BMDMs from WT mice, suggesting that CAD-derived itaconate influences succinate accumulation in LPS-induced macrophages (Fig. 6c).”
The paper relies on this without support.
The effects of exogenous itaconate on succinate accumulation reflect the physiological role of endogenous itaconate.
“In the cells studied, exogenous and endogenous, CAD-produced itaconate strongly correlated with succinate accumulation.”
The paper relies on this without support.
The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
“However, we consistently observed increased succinate downstream of itaconate production or administration in a variety of cell types.”
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?
In the citing paper
“Mechanistically LDHA-deficient T cells showed decreased acetyl-CoA levels and decreased histone H3 acetylation at the lysine 9 residue (H3K9Ac), a histone mark associated with active transcription, on the Ifng promoter.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
In the citing paper
“Mice with an T cell-specific LDHA deficiency produced less IFN-γ and were protected from immunopathology.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
In the citing paper
“The authors demonstrate that LDA, an enzyme that catalyzes the reversible conversion of pyruvate and NADH to lactate and NAD+, is induced in activated T cells and enhances histone acetylation of interferon gamma (Ifng) via the maintenance of acetyl-CoA levels to promote its expression 55.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
In the citing paper
“Furthermore, artificial acetyl-CoA reduction, through inhibition of ACLY, decreased IFN-γ expression and acetate supplementation, which augmented acetyl-CoA production, corrected H3K9Ac marks and IFN-γ expression in LDHA-deficient T cells.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
In the citing paper
“The generation of itaconate from the Krebs Cycle intermediate cis-aconitate contrasts with most other metabolite signals emanating from mitochondria, in that it primarily acts as a protective, anti-inflammatory metabolite55,59,60.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate Modulates Succinate Levels via SDH Inhibition
“increasing itaconate concentrations (0, 5, 10, and 25 mM)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
“increasing itaconate concentrations (0, 2.5, 5, 10, and 25 mM)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
“Succinate inhibits HIF-1␣ signaling through inhibition of PHD2”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
“succinate acts as a regulatory signal enhancing Il-1 expression through stabilization of HIF-1␣”
Citations
Cites
R: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,893
Pathogen Recognition and Innate Immunity
Akira, S., Uematsu, S., & Takeuchi, O. (2006) · Cell · doi:10.1016/j.cell.2006.02.015 · Cited by 12,401
Macrophage plasticity and polarization: in vivo veritas
Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijević, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N. J., Smith, A. C., et al. (2014) · Nature · doi:10.1038/nature13909 · Cited by 2,907 · cited 3×
“Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, in particular those that regulate succinate levels, which, in turn, can influence HIF signaling or other pathways (13, 25, 40, 41).”
BackgroundGiard, D. J., Aaronson, S. A., Todaro, G. J., Arnstein, P., Kersey, J. H., Dosik, H., & Parks, W. P. (1973) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/51.5.1417 · Cited by 2,336
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108
Jha, A. K., Huang, S. C.-C., Sergushichev, A., Lampropoulou, V., Ivanova, Y., Loginicheva, E., Chmielewski, K., Stewart, K. M., Ashall, J., Everts, B., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.005 · Cited by 2,066
Metabolic reprogramming in macrophages and dendritic cells in innate immunity
Kelly, B., & O'Neill, L. A. (2015) · Cell Research · doi:10.1038/cr.2015.68 · Cited by 1,876
Cited by
Sorted by citations
Items 301–400 of 525
Patiño‐Martínez, E., Nakabo, S., Jiang, K., Carmona‐Rivera, C., Tsai, W. L., Claybaugh, D., Yu, Z., Romero, A., Bohrnsen, E., Schwarz, B. H., et al. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2400241 · Cited by 18
Exploring the evolutionary roots and physiological function of itaconate
Cordes, T., & Metallo, C. M. (2020) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2020.11.005 · Cited by 18
Self-citationEhlers, G., Tödtmann, A. M., Holsten, L., Willers, M., Heckmann, J., Schöning, J., Richter, M., Heinemann, A. S., Pirr, S. M., Heinz, A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57357-w · Cited by 20
Self-citationFedotcheva, N. I., & Nv, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169069 · Cited by 17
Zhang, M., Xie, R., Wang, H., Wen, X., Wang, J., He, L., Zhang, M., & Yang, X. (2023) · Molecules · doi:10.3390/molecules28031060 · Cited by 17
Metabolic response to CNS infection with flaviviruses
Dobrzyńska, M., Moniuszko-Malinowska, A. M., & Skrzydlewska, E. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02898-4 · Cited by 20
Itaconate as a key regulator of respiratory disease
Michalaki, C., Albers, G. J., & Byrne, A. J. (2023) · Clinical & Experimental Immunology · doi:10.1093/cei/uxad127 · Cited by 17
Pro-inflammatory macrophage activation does not require inhibition of oxidative phosphorylation
Ball, A. B., Jones, A. E., Nguyễn, K. B., Rios, A., Marx, N., Hsieh, W. Y., Yang, K., Desousa, B. R., Kim, K. K. O., Veliova, M., et al. (2025) · EMBO Reports · doi:10.1038/s44319-024-00351-y · Cited by 22
Self-citationDivakaruni, A. S., Andreyev, A. Y., Rogers, G. W., & Murphy, A. N. (2018) · Analytical Biochemistry · doi:10.1016/j.ab.2017.09.019 · Cited by 18
Self-citationNRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA
Rajendiran, A., Subramanyam, S. H., Klemm, P., Jankowski, V., van Loosdregt, J., Vastert, S. J., Vollbach, K., Wagner, N., Tenbrock, K., & Ohl, K. (2022) · Antioxidants · doi:10.3390/antiox11122426 · Cited by 19
Metabolic reprogramming and immune regulation in viral diseases
Ganesh, G. V., & Ramkumar, K. M. (2021) · Reviews in Medical Virology · doi:10.1002/rmv.2268 · Cited by 17
Metabolic orchestration of T lineage differentiation and function
Yong, C. S. M., Moussa, D. A., Cretenet, G., Kinet, S., Dardalhon, V., & Taylor, N. N. (2017) · FEBS Letters · doi:10.1002/1873-3468.12849 · Cited by 16
Effect of pH and buffer on substrate binding and catalysis by cis-aconitate decarboxylase
Zhao, M., Chen, C., Blankenfeldt, W., Peßler, F., & Büssow, K. (2025) · Scientific Reports · doi:10.1038/s41598-025-89341-1 · Cited by 15
Antitumor effect of dimethyl itaconate on thymic carcinoma by targeting LDHA-mTOR axis
Hayashi, K., Nakazato, Y., Ouchi, M., Fujita, T., Endou, H., & Chida, M. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119847 · Cited by 15
Dimethyl itaconate alleviates the pyroptosis of macrophages through oxidative stress
Huang, S., Guo, D., Jia, B., Cai, G., Yan, J., Lu, Y., & Yang, Z. (2021) · BMC Immunology · doi:10.1186/s12865-021-00463-3 · Cited by 15
Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo
Oh, T. S., Hutchins, D. C., Mainali, R., Goslen, K. H., & Quinn, M. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.748375 · Cited by 16
Tissue-specific macrophage immunometabolism
Ben-Arosh, H., & Avraham, R. (2023) · Current Opinion in Immunology · doi:10.1016/j.coi.2023.102369 · Cited by 15
Itaconate: A promising precursor for treatment of neuroinflammation associated depression
Liu, R., Gong, Y., Xia, C., Cao, Y., Zhao, C., & Zhou, M. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115521 · Cited by 16
Metabolomic studies reveal an organ-protective hibernation state in donor lungs preserved at 10 °C
Wang, A., Ali, A., Baciu, C., Bellissimo, C. A., Siebiger, G., Yamanashi, K., Montagne, J. A., Garza, G., Goligher, E. C., Keshavjee, S. H., et al. (2024) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2024.08.015 · Cited by 16
Itaconate as an inflammatory mediator and therapeutic target in cardiovascular medicine
Diotallevi, M., Ayaz, F., NICOL, T., & Crabtree, M. J. (2021) · Biochemical Society Transactions · doi:10.1042/bst20210269 · Cited by 15
Itaconate promotes mitophagy to inhibit neuronal ferroptosis after subarachnoid hemorrhage
Wang, G., Li, Z., Han, W., Tian, Q., Liu, C., Jiang, S., Xiang, X., Zhao, X., Wang, L., Liao, J., et al. (2025) · APOPTOSIS · doi:10.1007/s10495-025-02077-1 · Cited by 14
Lin, M., Wang, J., Chai, Y., Chen, X., Zhao, D., Xie, Z., Jiang, J., Li, H., Huang, L., Xing, S., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.08.001 · Cited by 14
Casey, A. M., & Murphy, M. P. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166481 · Cited by 14
Cui, Y., Li, Z., Ni, L., Yu, S., Shan, X., Hu, P., Ji, Z., Jing, W., Zhou, Y., Wang, B., et al. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2300209 · Cited by 14
Li, T., Li, J., Qin, Y., Liu, R., Xu, X., Li, X., Li, L., Feng, B., Yang, L., & Yang, C. (2024) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.52080 · Cited by 14
Tan, B., Malu, S., & Roth, K. D. W. (2020) · Journal of Chromatography B · doi:10.1016/j.jchromb.2020.122120 · Cited by 14
Tracing insights into human metabolism using chemical engineering approaches
Cordes, T., & Metallo, C. M. (2016) · Current Opinion in Chemical Engineering · doi:10.1016/j.coche.2016.08.019 · Cited by 14
Self-citationEvans, V. A., & O'Neill, L. A. J. (2025) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-062624-013520 · Cited by 16
Trained immunity: a cutting edge approach for designing novel vaccines against parasitic diseases?
Zhu, J., Liu, J., Yan, C., Wang, D., & Pan, W. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1252554 · Cited by 13
Fujii, J. (2024) · Free Radical Research · doi:10.1080/10715762.2024.2407147 · Cited by 13
Why and how citrate may sensitize malignant tumors to immunotherapy
Icard, P., Prieto, M., Coquerel, A., Fournel, L., Gligorov, J., Noel, J., Mouren, A., Dohan, A. J. J., Alifano, M., & Simula, L. (2024) · Drug Resistance Updates · doi:10.1016/j.drup.2024.101177 · Cited by 14
Emerging role of the itaconate-mediated rescue of cellular metabolic stress
Sun, D., & Chang, H. (2021) · Tzu Chi Medical Journal · doi:10.4103/tcmj.tcmj_79_21 · Cited by 13
Zhang, Y., Tang, J., Wu, M., Zhou, X., Wang, S., Ye, H., Xiang, W., Zhang, Q., & Cai, T. (2022) · Food Bioscience · doi:10.1016/j.fbio.2022.102185 · Cited by 13
Lipopolysaccharide Tolerance in Human Primary Monocytes and Polarized Macrophages
Li, H., Breedijk, A. J., Dietrich, N., Nitschke, K., Jarczyk, J., Nuhn, P., Krämer, B. K., Yard, B. A., Leipe, J., & Hauske, S. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512196 · Cited by 15
Xu, M., Jiang, P., Sun, H., Yuan, X., Gao, S., Guo, J., Zhao, C., Hu, X., Liu, X., & Fu, Y. (2020) · PubMed Central · doi:10.22038/ijbms.2020.44151.10346 · Cited by 13
Itaconate family-based host-directed therapeutics for infections
Yuk, J., Park, E., Kim, I. S., & Jo, E. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1203756 · Cited by 14
Macrophage immunometabolism: emerging targets for regrowth in aging muscle
Fennel, Z. J., O’Connell, R. M., & Drummond, M. J. (2025) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00403.2024 · Cited by 13
Navigating immune cell immunometabolism after liver transplantation
Zhang, W., Liu, Z., & Xu, X. (2021) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2021.103227 · Cited by 12
New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease
de Jong, R., Tenbrock, K., & Ohl, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814173 · Cited by 14
Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication
Hafner, A., Meurs, N., Garner, A., Azar, E., Kannan, A., Passalacqua, K. D., Nagrath, D., & Wobus, C. E. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1011909 · Cited by 12
Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation
Li, Y., Singh, S., Breckenridge, H. A., Cui, T. X., Vigil, T. M., Kreger, J. E., Lei, J., Wong, H. K. A., Sajjakulnukit, P., Zhou, X., et al. (2024) · Mucosal Immunology · doi:10.1016/j.mucimm.2024.08.001 · Cited by 12
Itaconate and its derivatives as anti-pathogenic agents
Mazraani, R. A. A. D. A., Malys, N., & Malienė, V. (2025) · RSC Advances · doi:10.1039/d4ra08298b · Cited by 13
Photoinducible Oncometabolite Detection
Kulkarni, R. A., Briney, C. A., Crooks, D. R., Bergholtz, S. E., Mushti, C., Lockett, S., Lane, A. N., Fan, T. W. ‐., Swenson, R. E., Linehan, W. M., et al. (2018) · ChemBioChem · doi:10.1002/cbic.201800651 · Cited by 12
Liu, M., Yang, X., Zeng, C., Zhao, H.-K., Li, J., Hou, Z.-S., & Wen, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031340 · Cited by 13
Liu, J., Guo, X., Yang, L., Tao, T., Cao, J., Hong, Z., Zeng, F., Lu, Y., Lin, C., & Qin, Z. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.889292 · Cited by 12
The potential of using itaconate as treatment for inflammation-related heart diseases
Ku, H., Shen, T.-C., & Cheng, C. (2021) · Tzu Chi Medical Journal · doi:10.4103/tcmj.tcmj_83_21 · Cited by 11
IRG1/Itaconate induces metabolic reprogramming to suppress ER-positive breast cancer cell growth.
Wang, H., Chang, W., Lee, D., Li, X., & Hung, M. (2023) · PubMed Central · Cited by 11
Anti-Necroptotic Effects of Itaconate and its Derivatives
Ni, S.-T., Li, Q., Chen, Y., Shi, F., Wong, T.-S., Yuan, L.-S., Xu, R., Gan, Y.-Q., Lu, N., Li, Y., et al. (2023) · Inflammation · doi:10.1007/s10753-023-01909-z · Cited by 11
Itaconate as a key player in cardiovascular immunometabolism
Shan, W., Cui, J., Song, Y., Yan, D., Feng, L., Jian, Y., Yi, W., & Sun, Y. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.04.218 · Cited by 12
The cell autonomous and non-autonomous roles of itaconate in immune response
Chen, C., & Li, X. (2024) · Cell Insight · doi:10.1016/j.cellin.2024.100224 · Cited by 11
Metabolomic and Lipidomic Analysis of Bone Marrow Derived Macrophages
Seim, G. L., John, S., & Fan, J. (2020) · BIO-PROTOCOL · doi:10.21769/bioprotoc.3693 · Cited by 11
Qiao, K., Page, L. M. L., & Chaumeil, M. M. (2021) · Metabolites · doi:10.3390/metabo11070410 · Cited by 11
The role and therapeutic potential of itaconate in lung disease
He, R., Zuo, Y., Yi, K., Liu, B., Song, C., Li, N., & Geng, Q. (2024) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00642-1 · Cited by 11
Dzik, J. (2021) · Acta Biochimica Polonica · doi:10.18388/abp.2020_5683 · Cited by 10
Krebs Cycle Rewired: Driver of Atherosclerosis Progression?
Liang, Y., Chen, Y., Lü, L., Zhang, S., Xiao, J., & Wei, D. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666210806105246 · Cited by 11
Huang, K., & Aye, Y. (2024) · Communications Chemistry · doi:10.1038/s42004-024-01282-4 · Cited by 9
McBride, M. A., Burelbach, K. R., Patil, T. K., Owen, A. M., Luan, L., Bohannon, J. K., Hernandez, A., Stothers, C. L., Trenary, I. A., Rahim, M., et al. (2024) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiae198 · Cited by 10
Engineering immunity using metabolically active polymeric nanoparticles
Griffin, K. V., Saunders, M. N., Lyssiotis, C. A., & Shea, L. D. (2024) · Trends in biotechnology · doi:10.1016/j.tibtech.2024.11.016 · Cited by 9
ZFTA–RELA ependymomas make itaconate to epigenetically drive fusion expression
Natarajan, S. K., Lum, J., Skeans, J. H., Nenwani, M., Eyunni, S., Mota, M., Bayliss, J. M., Deogharkar, A., Hamanishi, E. T., Pun, M. J., et al. (2026) · Nature · doi:10.1038/s41586-025-10005-1 · Cited by 11
Fuchs, A. L., Miller, I. R., Schiller, S. M., Ammons, M. C. B., Eilers, B. J., Tripet, B., & Copié, V. (2020) · Cells · doi:10.3390/cells9102260 · Cited by 9
Zhu, X., Zhang, Y., Liu, H., Yang, G., & Li, L. (2023) · BMC Microbiology · doi:10.1186/s12866-023-02914-w · Cited by 9
Cramer-Morales, K. L., Heer, C. D., Mapuskar, K. A., & Domann, F. E. (2020) · Journal of Experimental Pathology · doi:10.33696/pathology.1.009 · Cited by 10
Yao, Y. Y., Zhu, Z. X., Ai, C. H., Liang, X. Y., Yang, G., Liu, T. D., Zhang, H. Y., Yan, H. J., Xia, J., & He, M. L. (2023) · Aquaculture · doi:10.1016/j.aquaculture.2023.740147 · Cited by 8
Antifibrotic Function of Itaconate-Based Degradable Polyester Materials
Froom, Z. S. C. S., Medd, K., Wheeler, B. P., Osborne, N. D., Rempe, C. N., Woodworth, K. E., Charron, C., & Huyer, L. D. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.4c02444 · Cited by 8
Liu, Q., Liu, A. A., Leng, S., Zhang, X., Wang, X., Zhang, C., Wang, S., Peng, J., & Feng, Q. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003586 · Cited by 8
Zhang, T., Klair, A., Tang, Z., Tripka, A., Luo, S., Reyes, A. V., Lee, J., Gundran, K., Noll, S. E., Wang, X., et al. (2025) · Science Advances · doi:10.1126/sciadv.adt7463 · Cited by 9
Iaconis, A., Molinari, F., Fusco, R., & Paola, R. D. (2025) · Biomedicines · doi:10.3390/biomedicines13071708 · Cited by 9
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
Metabolite and nutrient regulation of macrophages in obesity and metabolic disease
Sprenkle, N. T., & Mills, E. L. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01292-4 · Cited by 11
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
Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5
Chen, F., Willenbockel, H. F., & Cordes, T. (2023) · Metabolites · doi:10.3390/metabo13030331 · Cited by 10
Self-citationCox, J. H., McCain, R. S., Tran, E., Swaminathan, S., Smith, H. H., Piroli, G. G., Shtutman, M. S., Walla, M. D., Cotham, W. E., & Frizzell, N. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00354.2023 · Cited by 9
Cardiac resident macrophages: The core of cardiac immune homeostasis
Cai, W., Lian, L., Li, A., Zhang, Q., Li, M., Zhang, J., & Xie, Y. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111169 · Cited by 8
Sano, M., Yada, R., Nomura, Y., Kusukawa, T., Andō, H., Matsumoto, K., Wada, K., Tanaka, T., Ohara, H., & Aso, Y. (2020) · Microorganisms · doi:10.3390/microorganisms8050648 · Cited by 8
Chang, M., Wang, Q., Liu, X., Shi, X., & Xu, G. (2021) · Analytical Chemistry · doi:10.1021/acs.analchem.1c01101 · Cited by 8
The role of glycolysis in inflammation
Dehantschutter, E. T., & Taylor, C. T. (2026) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00113.2026 · Cited by 7
Greasing the inflammatory pathogenesis of viral pneumonias in diabetes
Damen, M. S. M. A., Alarcon, P. C., SHAH, A. S., & Divanovic, S. (2022) · Obesity Reviews · doi:10.1111/obr.13415 · Cited by 10
Watermann, P., Kalsi, G. K., Dringen, R., & Arend, C. (2024) · Neurochemical Research · doi:10.1007/s11064-024-04263-0 · Cited by 6
Hayashi, Y., Saeki, A., Yoshimoto, S., Yano, E., Yasukochi, A., Kimura, S., Utsunomiya, T., Minami, K., Aso, Y., Hatakeyama, Y., et al. (2025) · Antioxidants and Redox Signaling · doi:10.1089/ars.2024.0629 · Cited by 6
Poulsen, C., Roy, D. G., & Olagnier, D. P. (2024) · Human Molecular Genetics · doi:10.1093/hmg/ddae177 · Cited by 7
4-Octyl Itaconate Modulates Dendritic Cells Function and Tumor Immunity via NRF2 Activation
Zhu, B., Zhu, L., Ge, Z., Zheng, S., Dai, X., Feng, D., Tan, L., Sha, P., & Yao, Y. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s516085 · Cited by 6
Liu, Y., Zhang, P., Kong, W., Li, J., Yang, H., Bai, H., Fan, G., Cao, X., & Li, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1767601 · Cited by 9
Diotallevi, M., Outeiral, C., Patel, P., Purvis, G. S. D., Chuaiphichai, S., Nicol, T., Ayaz, F., Nissley, D. A., Krasnoselska, G. O., Hester, S., et al. (2026) · Nature Metabolism · doi:10.1038/s42255-026-01492-1 · Cited by 6
The alkylation of AIM2 by itaconate mediates macrophage PANoptosis during sepsis
Ma, J. J., Chen, Y., Wang, P., Zhang, Y., Li, Y., Tu, Q., Zhao, X., Yao, X., Li, F., Yuan, Y., et al. (2026) · Cellular and Molecular Immunology · doi:10.1038/s41423-026-01414-x · Cited by 6
Effect of age on metabolomic changes in a model of paclitaxel‐induced peripheral neurotoxicity
Bonomo, R., Canta, A., Chiorazzi, A., Carozzi, V., Meregalli, C., Pozzi, E., Alberti, P., Frampas, C., van der Veen, D. R., Marmiroli, P., et al. (2023) · Journal of the Peripheral Nervous System · doi:10.1111/jns.12609 · Cited by 8
Ma, J., Ao, Y., Yue, Z., Wang, Z., Hou, X., Li, H., Wang, H., Luo, S., He, J., Duan, Z., et al. (2025) · Advanced Science · doi:10.1002/advs.202413546 · Cited by 7
Fu, T., Qin, S., He, H., Zhang, K., Zhang, W., Tang, X., & Wu, W. (2022) · Metabolites · doi:10.3390/metabo12100981 · Cited by 6
The Impact of Krebs Cycle Intermediates on the Endocrine System and Immune System: A Comparison
Arneth, B. M. (2023) · Endocrines · doi:10.3390/endocrines4010016 · Cited by 6
Role of IRG1 in Regulating Pro-inflammatory and Pro-labor Mediators in Human Myometrium
Lim, R., & Lappas, M. (2020) · Reproductive Sciences · doi:10.1007/s43032-019-00133-1 · Cited by 6
The Pivotal Role of Macrophages in Metabolic Distress
Roberts, J., Fallon, P. G., & Hams, E. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.86474 · Cited by 8
Szeligowski, R. V., Miros, F. N., Saez, A., DeCiucis, M., Wagner, G. P., & Shen, H. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.17.496652 · Cited by 6
Dissecting S-itaconation at host–pathogen interactions with chemical proteomics tools
Liu, Z., & Wang, C. (2025) · Current Opinion in Microbiology · doi:10.1016/j.mib.2025.102579 · Cited by 5
Preclinical insights into the potential of itaconate and its derivatives for liver disease therapy
Wu, X., Song, Y., Yuan, Z., & Wu, S. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156152 · Cited by 5
Yao, X., Liu, H., Duan, C., Zhang, Y., Wu, X., Li, B., Li, S., Gong, Y. Q., Liu, T., Wang, X., et al. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70450 · Cited by 5
A non-canonical immunometabolic function of BRD3 during sepsis
Wang, N., Liu, J., Wu, R., Chen, F., Yu, C., Zeh, H. J., Xiao, X., Wang, H., Billiar, T. R., Zeng, L., et al. (2025) · Developmental Cell · doi:10.1016/j.devcel.2025.09.016 · Cited by 5
Airway immunometabolic responses during pulmonary bacterial and viral infections
Wadhwa, R., Tang, E. W., Wong, L. Y. R., & Lung, T. W. F. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116614 · Cited by 5
Tian, Z., Huang, Y., Wang, Y., Zhao, C., Zhou, Z., Yang, H., & Qiu, Y. (2026) · Interdisciplinary medicine · doi:10.1002/inmd.70083 · Cited by 8
Metabolic control of neuroinflammation: focus on itaconate and its derivatives in CNS disorders
Wang, Y. L., Liu, S., Zhu, W., Hao, P., Xu, J., Mai, D., Chen, R., Han, H., Bian, X., & Wang, B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1726379 · Cited by 5
Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme
Mailloux, R. J. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.02.050 · Cited by 5
Molecular Dialogues in the Mitochondria–Microbiome Crosstalk: Metabolites, Signaling, and Immunity
Tenchov, R. (2026) · Comprehensive physiology · doi:10.1002/cph4.70164 · Cited by 6
Metadata
- Authors
- Cordes, T., Wallace, M., Michelucci, A., Divakaruni, A. S., Sapcariu, S. C., Sousa, C., Koseki, H., Cabrales, P., Murphy, A. N., Hiller, K., & Metallo, C. M.
- Affiliations
- University of California San Diego (US)
- University of Luxembourg (LU)
- RIKEN Center for Integrative Medical Sciences (JP)
- Corresponding author
- Metallo, Christian M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 291
- Issue
- 27
- Pages
- 14274-14284
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4933182
- OpenAlex
- W2361586644
- Semantic Scholar
- e5517dd16c4dff72218eace800e1b0913a233bce
- Cited by
- 526
- References
- 52
- Citations by year
- 2026: 55 · 2025: 60 · 2024: 68 · 2023: 55 · 2022: 58 · 2021: 69 · 2020: 64 · 2019: 42 · 2018: 27 · 2017: 23 · 2016: 5
- FWCI
- 19.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (R01CA188652, P01DK054441)
- National Institute of Allergy and Infectious Diseases (R01AI082610)
- National Heart, Lung, and Blood Institute (R53HL123015, P01HL110900, R01HL052684)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
- Keywords
- IRG1, itaconate, succinate accumulation, succinate dehydrogenase inhibition, cis-aconitate decarboxylase, TCA cycle, metabolic reprogramming, innate immunity, macrophages, lipopolysaccharide, electron transport chain, immunometabolism
- MeSH terms
- Animals, Cell Line, Hydro-Lyases, Lipopolysaccharides, Macrophages, Succinate Dehydrogenase, Succinates, Succinic Acid, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
