Menin is a corepressor of the LXR sterol sensors - one paper supplies three of this graph's twelve missing partners, and the function has never been written down here
also called menin LXR · menin lipogenesis · MEN1 SREBP-1c · menin hepatic steatosis
Three of the partners this graph was missing - LXR-alpha, LXR-beta and SREBP-1 - are not three discoveries. They are one experiment in one paper showing that menin switches OFF the genes that make fat. That is a job for menin this project had never recorded.
The same thing, for a scientist
The dispatch question was whether NR1H3 (LXR-alpha), NR1H2 (LXR-beta) and SREBF1 (SREBP-1) are one story or three unrelated screens. **They are one paper**: Cheng et al. 2015, all twelve IntAct records, all one figure set, HepG2 cells and mouse liver [E1][E2]. Menin binds LXR-alpha and LXR-beta, represses LXR transcriptional activity, and lowers the LXR target genes SREBP-1c, FASN and SCD-1; the same figure set shows LXR-alpha co-precipitating the coactivators **NCOA1/SRC-1 and EP300**, which is the competition the corepressor model needs [E1][E2]. It is **not a one-off**: menin represses LXR target genes ABCA1 and ABCG1 and lowers cellular cholesterol in colorectal cancer lines and in Men1-floxed;Vil1-Cre mouse colonic epithelium, an independent group, an independent tissue, and a genetic rather than transfection-based arm [E3]. Two further papers from the hepatic series put menin on PPAR-alpha as a **co-activator** [E4] and on SIRT1 recruitment [E5]. **This graph holds 1,806 entries and no menin function outside chromatin, endocrine neoplasia and leukaemia.** That is the finding: not a missing interactor, a missing job.
The twelve records, resolved to figures
IntAct's curation of this paper is figure-resolved, which is unusually good and makes the internal structure readable without the full text 1:
| partners | species / system | figure | type | expansion |
|---|---|---|---|---|
| MEN1 - NR1H3 | human HepG2 | Fig 4b | physical association | none |
| Men1 - Nr1h3 | mouse | Fig 4c (menin bait) | physical association | none |
| Men1 - Nr1h3 | mouse | Fig 4d (LXR-alpha bait - reciprocal) | physical association | none |
| MEN1 - NR1H3 | human HepG2 | SF5A | association | spoke |
| MEN1 - NR1H2 | human HepG2 | SF4a | physical association | none |
| Men1 - Nr1h2 | mouse | SF4b | physical association | none |
| MEN1 - SREBF1 | human HepG2 | SF6 | physical association | none |
| NR1H3 - NCOA1 / EP300 | human + mouse | F5A / SF5A | association | spoke |
Read this way the cluster is not three single-record partners. LXR-alpha has four records across two species with both directions curated. LXR-beta has two, in two species. SREBF1 has one.
The dispatch brief recorded one record each. The REST endpoint returns four, two and one. The count discrepancy is systematic across this beat and is treated in ana-the-unwritten-interactome-partners-are-better-observed-than-the-written-ones.
Where SREBF1 sits, and why it is the weakest of the three
SREBP-1c is the LXR target gene the paper is about. Cheng et al. report that menin overexpression reduces SREBP-1c, FASN and SCD-1 - that is the readout of LXR repression 2. A menin-SREBF1 co-immunoprecipitation in supplementary figure 6 therefore sits in an awkward position: SREBF1 is simultaneously a proposed binding partner and the downstream reporter of the pathway.
That is not a reason to discard it, but it is a reason to grade it below the LXRs. SREBF1's protein is also processed - a 1,147-residue ER-membrane precursor cleaved to a nuclear bHLH-zip form - and neither the abstract nor the IntAct record says which species was blotted. A pull-down of the precursor and a pull-down of the mature nuclear factor are different claims about where in the cell menin is acting.
What this means for a menin inhibitor, stated as a prediction and not as a finding
If menin represses LXR, then removing menin should de-repress LXR, raising SREBP-1c, FASN and SCD-1 in the liver and raising ABCA1/ABCG1 with cholesterol efflux in epithelium 23. The colorectal arm demonstrates exactly that with pharmacological menin inhibition: 'menin inhibition upregulated LXR-target genes, specifically ABCG1 and ABCA1' 3.
So a clinical menin inhibitor is predicted to move hepatic lipogenesis and cellular cholesterol handling, and no pivotal trial in this class has published a lipid panel. The prediction is cheap to test and the samples exist. It is written up separately as hyp-menin-inhibition-derepresses-lxr-target-genes-in-patients.
The honest counterweight: the hepatic work is transfection-heavy, HepG2 is a hepatoma line, and the menin-PPAR-alpha paper from the same group has menin acting as a co-activator on a different nuclear receptor in the same tissue 4. Menin is a scaffold whose sign depends on the partner, so 'menin inhibition de-represses lipogenesis' is one arm of a two-sided effect and could be cancelled by the PPAR-alpha arm pointing the other way.
| menin role | corepressor of LXR-alpha (NR1H3) and binder of LXR-beta (NR1H2); competes with the coactivators NCOA1/SRC-1 and EP300 on the same receptor |
|---|---|
| independent replication of direction | true |
| independent replication of physical interaction | false |
| intact records total | 12 |
| intact records non spoke | 7 |
| one story or three | ONE. All three partners come from one publication, one figure set, two cell systems - and the direction replicates independently in colorectal tissue. |
| shown for fusion | NO - nobody has looked in any KMT2A fusion, in any lineage. Every system here is hepatic or intestinal. |
| in this graph before | No menin function outside chromatin, endocrine neoplasia and leukaemia existed in 1,806 entries. |
| fetched | 2026-09-21 |
downstream genes repressed
[ "SREBF1 / SREBP-1c", "FASN", "SCD-1", "ABCA1", "ABCG1" ]
systems
[ "HepG2 hepatocellular carcinoma", "mouse liver", "HT-29 and HCT-15 colorectal carcinoma", "Men1-floxed;Vil1-Cre mouse colonic epithelium" ]
source publications
[ "25962847", "37627154", "22001208", "23867312" ]
- A menin inhibitor is predicted here to DE-REPRESS lipogenesis. In a child on a months-long course, alongside asparaginase and corticosteroids, which already drive hypertriglyceridaemia and hepatic steatosis, that is a plausible and entirely unmeasured additive toxicity.
- The opposite sign exists in the same tissue: menin co-activates PPAR-alpha. A net prediction requires both arms and nobody has measured them together.
- Reading three IntAct rows as three partners would have produced three thin entries and no mechanism. The count of partners was never the unit; the publication was.
- Do patients on revumenib, ziftomenib or bleximenib show a change in serum lipids, hepatic fat or cholesterol? No pivotal trial in this class has published a lipid panel, and banked samples exist.
- Does menin repress LXR in a haematopoietic cell at all? Every system in this literature is hepatic or intestinal, and LXR agonists are themselves under study in AML, so the sign in a blast is not predictable from the liver.
- Which menin surface binds LXR-alpha? If it is the MBM cavity that revumenib occupies, the drug displaces LXR-alpha directly and the prediction is strong; if it is elsewhere, menin degradation rather than pocket occupancy would be the operative mechanism, and the two drugs in this class differ in how much they degrade menin.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
All three of NR1H3, NR1H2 and SREBF1 reach this project through a single publication, PMID 25962847, whose twelve IntAct records are figure-resolved: MEN1-NR1H3 non-spoke in human HepG2 (Fig 4b) and in mouse in both directions (Fig 4c menin bait, Fig 4d LXR-alpha bait), MEN1-NR1H2 non-spoke in human (SF4a) and mouse (SF4b), MEN1-SREBF1 non-spoke in human (SF6), and spoke-expanded NR1H3-NCOA1 and NR1H3-EP300 rows (F5A/SF5A).
IntAct REST findInteractions/25962847 (Cheng et al. 2015), 12 records, figure-legend annotated, fetched 2026-09-21 · EMBL-EBI IntAct 2026What this evidence cannot show
One database on one day, REST endpoint (brief rule 93). Twelve records from ONE publication are twelve curated experiments, not twelve findings. The figure attributions are IntAct curator annotations and were not checked against the figures, because the full text is behind Elsevier and route 5 returns HTTP 403.
Evidence that argues against this (2)
- Two rows of this table are mis-described, and both errors flatter the record. Re-enumerated at the endpoint on 2026-09-21: the F5A spoke record EBI-11364853 pairs HUMAN NR1H3 (Q13133) with MOUSE Men1 (O88559), taxa 9606/10090 - a cross-species pair, not the 'human HepG2, SF5A' row the table lists - and the sf5a spoke record EBI-11364871 is a separate, entirely MOUSE record (Q9Z0Y9 against O88559, P70365 and B2RWS6). So 'NR1H3-NCOA1 and NR1H3-EP300 (F5A/SF5A)' is two different records in two different species collapsed into one table row, and the coactivator-competition argument rests on one human spoke record (EBI-11364853, mi 0.35-0.69) plus its mouse counterpart, not on a human and mouse replicate pair. EMBL-EBI IntAct 2026
- 'All twelve records' is twelve AT THIS ENDPOINT. Measured the same day, the REST-versus-PSICQUIC gap on the accessions in this cluster is Q13133 132 vs 40, P55055 75 vs 29 and P36956 93 vs 31 - so a reader coming to this mechanism through the query form used by this project's two earlier interactome analyses would see roughly a third of each protein's record and could reasonably have concluded the cluster was not there. The figure-resolved twelve is the best view available, not the whole view. EMBL-EBI IntAct and PSICQUIC 2026
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In HepG2 hepatoma cells and mouse liver (no haematopoietic system, no leukaemia), menin inhibits the transcriptional activity of LXR-alpha, menin overexpression reduces the LXR target genes SREBP-1c, FASN and SCD-1, and co-immunoprecipitation shows physical interaction between menin and LXR-alpha; the authors conclude menin is a corepressor of LXR-alpha and a negative regulator of hepatic lipogenesis.
Tumor suppressor Menin acts as a corepressor of LXRα to inhibit hepatic lipogenesis. · Cheng P, et al. · FEBS Lett 2015What this evidence cannot show
Abstract read this session; full text is Elsevier and route 5 (DOI resolution) returns HTTP 403, so the blots themselves were not seen and the figure attributions come from IntAct's curator annotations. HepG2 hepatocellular carcinoma cells and mouse liver - no haematopoietic system, no KMT2A fusion, no leukaemia of any kind (brief rule 73). Transient transfection and overexpression throughout. New to this graph (checked with scripts/check-citation-reuse.py). Transient transfection assays are the stated method for the transcriptional arm, so the repression is measured on reporter constructs and overexpressed receptor.
Evidence that argues against this (1)
- The same group previously reported menin as a CO-ACTIVATOR of PPAR-alpha in the same tissue, preventing liver steatosis by the opposite sign of regulation. Menin's effect on lipid handling is therefore partner-dependent and not a single direction, and a menin-inhibition prediction built on the LXR arm alone ignores the PPAR-alpha arm. Cheng P et al. 2011
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Independently, in HT-29 and HCT-15 colorectal cancer lines and in Men1-floxed;Vil1-Cre mouse colonic epithelium, menin inhibition upregulated the LXR target genes ABCG1 and ABCA1 and reduced total cellular cholesterol, replicating the menin-represses-LXR direction in a different tissue, a different group, and with a genetic as well as a pharmacological arm.
Menin Maintains Cholesterol Content in Colorectal Cancer via Repression of LXR-Mediated Transcription. · Nyul TE, et al. · Cancers (Basel) 2023What this evidence cannot show
Abstract read this session. Colorectal cancer lines and mouse colonic epithelium - no haematopoietic system, no KMT2A fusion (brief rule 73). The Men1-floxed;Vil1-Cre mice had no distinct baseline phenotype, so the genetic arm is a gene-expression and cholesterol-content result rather than a phenotype. This is replication of a direction, not of the physical interaction: the paper's evidence is RNA-Seq and cholesterol assay, not co-immunoprecipitation.
Evidence that argues against this (1)
- The pharmacological half of this replication may not be a menin result at all. Phillips et al. 2019 identify lanosterol synthase as the direct molecular target of MI-2 and show its antitumour activity in glioma is largely independent of menin, acting through suppressed cholesterol synthesis and generation of the endogenous LXR ligand 24,25-epoxycholesterol. Cholesterol depletion plus LXR-target induction IS the off-target signature of that chemotype. Nyul et al.'s abstract does not name the inhibitor or its concentration, so the 'pharmacological as well as genetic' framing that makes this replication persuasive is the part that cannot presently be attributed to menin. Phillips RE et al. 2019
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
From the same hepatic series, menin co-activates PPAR-alpha and prevents liver steatosis - the opposite sign of lipid regulation from the LXR arm, in the same tissue.
Menin prevents liver steatosis through co-activation of peroxisome proliferator-activated receptor alpha. · Cheng P, et al. · FEBS Lett 2011What this evidence cannot show
Abstract only. Mouse liver and hepatoma lines; no haematopoietic system (brief rule 73). Recorded here as the counterweight to the LXR prediction rather than as support for it.
Evidence that argues against this (2)
- Menin's nuclear-receptor coactivation is not specific to PPAR-alpha, and the human loss-of-function phenotype is not the one either hepatic arm predicts. MEN1 mutation carriers have significantly higher HOMA insulin resistance than matched controls (3.0 +/- 2.0 vs 2.0 +/- 1.0) and a higher prevalence of impaired fasting glucose (17% vs 6%), in a study that describes menin as a coactivator of PPAR-GAMMA and of the vitamin D receptor. So 'menin co-activates PPAR-alpha' is one member of a set of nuclear-receptor coactivations, and the only human germline data point is a metabolic phenotype that neither the PPAR-alpha nor the LXR arm was built to explain. van Wijk JP et al. 2012
- Whole-animal menin loss does not move lipid in the direction the steatosis arm implies. In intestinal-epithelium-specific Men1 knockout mice, Men1 deficiency PROTECTS against high-fat-diet obesity by de-repressing Ces1g, increasing triglyceride hydrolysis and activating fatty-acid beta-oxidation, and MI-463 recapitulates it. 'Menin prevents steatosis, so menin inhibition should worsen it' is therefore not the organism-level prediction, and the tissue in which menin is removed decides the sign. Cao X et al. 2026
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation, a third menin-lipid mechanism in the same tissue from a different group.
Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation. · Cao Y, et al. · J Hepatol 2013What this evidence cannot show
Abstract only; mouse liver. Included to establish that menin's hepatic lipid role is a small but real literature rather than one paper, not to assert a mechanism this entry has read in detail.
Evidence that argues against this (1)
- There are now four unreconciled menin-cofactor mechanisms in lipid tissue and no experiment separating them: corepression of LXR-alpha (Cheng 2015), coactivation of PPAR-alpha (Cheng 2011), SIRT1 recruitment (this item), and - added since - HDAC1 recruitment with LXR-beta at Ces1g in intestinal epithelium (Cao 2026). Each is 'menin recruits a deacetylase to a nuclear receptor in a metabolic tissue'. A scaffold with four such mechanisms and no cross-test is being described generically; citing this item to show 'the literature is real rather than one paper' counts papers, and the thing that is missing is not papers but an experiment that excludes one mechanism in favour of another. Cao X et al. 2026
- E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
As of 2026-09-21, PubMed returns 3 records for menin[tiab] AND (LXR OR 'liver X receptor' OR NR1H3 OR NR1H2)[tiab] and 8 for menin[tiab] AND (lipogenesis OR steatosis OR SREBP OR 'lipid metabolism')[tiab], against 1,264 for menin[tiab] alone - so the literature exists, is small, and the intersection query composes.
What this evidence cannot show
Titles and abstracts only; supporting figures not searched (brief rule 80). Name list tried: menin, LXR, liver X receptor, NR1H3, NR1H2, lipogenesis, steatosis, SREBP, lipid metabolism. MEN1 as an operand was run separately and behaves differently because it also retrieves the syndrome. Operand control (brief rule 67): menin[tiab] alone returns 1,264, so the small intersections are real and not a non-composing query.
Evidence that argues against this (1)
- These two counts are not title-and-abstract counts, and the caveat that says they are is wrong. Read back from PubMed's own querytranslation on 2026-09-21, a field tag written after a parenthesised OR group is DROPPED: 'menin[tiab]' translates to "menin"[Title/Abstract], but '(LXR OR "liver X receptor" OR NR1H3 OR NR1H2)[tiab]' expands to a chain of [All Fields] terms with no [Title/Abstract] anywhere in it. So each of these is menin-in-title-or-abstract intersected with the other term ANYWHERE in the record, MeSH headings and author keywords included. The counts reproduce exactly today (3 and 8), so they are stable; they are a ceiling on the tiab-by-tiab intersection the claim describes, and brief rule 80's full-text bound is unaffected. NCBI PubMed 2026
a menin function outside chromatin, endocrine neoplasia and leukaemia - the first in this graph
a menin-driven metabolic axis that is not downstream of the fusion
third menin-lipid mechanism in the same tissue (PMID 23867312)
predicted de-repression of LXR target genes; no lipid panel published in this drug class
the receptor the mechanism is about
the paralogue arm; the one that would put the axis in a haematopoietic cell
the target gene whose reduction is the mechanism's readout, and a candidate partner in the same figure set
the mechanism the prediction is derived from
tests whether the hepatic/intestinal mechanism operates in patients
the menin-inhibitor lipid absence this mechanism rested on is gone: MI-463 and intestinal Men1 deletion limit lipid absorption through LXR-beta (PMID 42579365), and MI-2's cholesterol phenotype is an off-target lanosterol-synthase effect largely independent of menin (PMID 30923116)