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Pi3k/akt/mtor Signaling in Cancer / Neuroendocrine Tumor Research Advances · Journal article
Journal of Clinical Investigation · August 11, 2026
Encouraging direction, but not yet definitive.
This preclinical study identifies menin as a negative regulator of intestinal lipid absorption in mice, demonstrating that Men1 deficiency or pharmacological menin inhibition (MI-463) protects against high-fat diet-induced obesity by elevating carboxylesterase 1 expression and promoting fatty acid catabolism. The mechanism is mechanistically detailed and validated in human intestinal organoid-on-chip, but lacks in vivo efficacy data for the drug candidate in mice or any human efficacy signal.
Genetic knockout mouse model with mechanistic validation and pharmacological confirmation in organoid system. Mice with intestinal epithelial cell-specific Men1 knockout; human-derived intestinal organoid-on-chip system. Intervention: IEC-specific Men1 knockout; pharmacological menin inhibition with MI-463. Compared with: Wild-type mice on high-fat diet; untreated organoid controls.
IEC-specific Men1 knockout mice were protected against high-fat diet-induced obesity Men1 deficiency elevated carboxylesterase 1 (CES1) expression in intestinal epithelial cells Increased CES1 promoted triglyceride hydrolysis and reduced intracellular triglyceride storage
No human clinical data; no safety or tolerability data for menin inhibition reported Pharmacological menin inhibition with MI-463 recapitulated metabolic effects of Men1 deletion
This work identifies menin inhibition as a potential therapeutic target for obesity, but evidence is confined to animal models and ex vivo human tissue. Translation to human efficacy and safety requires clinical investigation.
A mechanistically rigorous preclinical study demonstrating that menin inhibition reduces high-fat diet-induced weight gain in mice through intestinal lipid absorption limitation, supported by organoid validation but lacking human efficacy data.
As stated by the source record.
Quoted from the source exactly as published.
This work identifies menin inhibition as a potential therapeutic target for obesity, but evidence is confined to animal models and ex vivo human tissue. Translation to human efficacy and safety requires clinical investigation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Intestinal lipid metabolism is essential for systemic energy homeostasis, and its modulation is emerging as a therapeutic strategy for obesity. Menin, a scaffold protein that regulates chromatin remodeling and gene expression, is abundantly expressed in intestinal epithelial cells (IECs), but its metabolic role remains underexplored. Here, we generated IEC-specific Men1 knockout mouse and found that Men1 deficiency protected against high-fat diet-induced obesity, accompanied by elevated carboxylesterase 1 (CES1) expression in IECs. Increased CES1 promoted triglyceride (TG) hydrolysis and reduced intracellular TG storage, thereby limiting the lipid substrate pool required for ApoB48-dependent chylomicron assembly. Although lipid hydrolysis was enhanced, steady-state free fatty acid levels were not increased; instead, Men1 deficiency activated fatty acid β-oxidation programs and increased etomoxir-sensitive fatty acid–dependent mitochondrial respiration, supporting enhanced fatty acid catabolism. Mechanistically, menin recruited histone deacetylase 1 and interacted with the nuclear receptor LXRβ to suppress Ces1g transcription, thereby sustaining efficient intestinal lipid absorption. Pharmacological inhibition of menin with MI-463 recapitulated the metabolic effects of inducible Men1 deletion. In a human gut organoid-on-chip system, MI-463 dose-dependently increased CES1 expression and markedly reduced lipid accumulation. Collectively, our findings identify menin as a regulator of intestinal lipid metabolism and suggest menin inhibition as a potential therapeutic strategy for obesity-related metabolic disorders.
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