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Metabolism and Genetic Disorders · Journal article
Nature Communications · August 14, 2026
Raises a question worth testing. It does not answer one.
This is a mechanistic discovery study in cultured cells and animal models identifying DHODH inhibition as a trigger for macropinocytosis-mediated drug resistance through a lactylation-driven TERF2IP–EGFR–albumin axis. The work proposes a rationale for combination therapy but does not report clinical efficacy data or quantitative efficacy endpoints for the proposed combinations.
Mechanistic discovery study combining CRISPR-Cas9 screening, small-molecule screening, and preclinical in vitro and in vivo models. Cancer cell lines and tumor-bearing animal models; specific cell types and tumor histologies not specified in abstract.. Intervention: DHODH inhibition (small-molecule inhibitor); co-administration with macropinocytosis blockers or EGFR inhibitors. Compared with: DHODH inhibition alone versus combination with macropinocytosis or EGFR inhibition; specific comparator arms not detailed.
DHODH inhibition triggers metabolic reprogramming toward glycolysis and lactate accumulation Lactate promotes lysine 208 lactylation of TERF2IP, activating epiregulin transcription Epiregulin activation drives EGFR-dependent macropinocytosis
Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.
This mechanistic finding suggests a resistance pathway to DHODH inhibitors in cancer. If validated clinically, it could support exploration of combination regimens pairing DHODH inhibitors with EGFR or macropinocytosis inhibitors, but the evidence remains preclinical.
This is a mechanistic discovery study identifying a previously unknown metabolic pathway in cell culture and animal models, proposing a novel resistance mechanism rather than testing a clinical intervention or providing evidence for practice change.
As stated by the source record.
This mechanistic finding suggests a resistance pathway to DHODH inhibitors in cancer. If validated clinically, it could support exploration of combination regimens pairing DHODH inhibitors with EGFR or macropinocytosis inhibitors, but the evidence remains preclinical.
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.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Macropinocytosis enables cancer cells to scavenge extracellular nutrients and contributes to tumor progression, but its role in chemoresistance remains poorly characterized. Through CRISPR-Cas9 and small-molecule screens, we identify inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis, as an inducer of macropinocytosis. Mechanistically, DHODH inhibition triggers metabolic reprogramming toward glycolysis and lactate accumulation. This metabolic shift promotes lysine 208 lactylation of telomeric repeat-binding factor 2-interacting protein (TERF2IP), unveiling its moonlighting function in transcriptional activation of epiregulin, which activates EGFR signaling to promote macropinocytosis. Macropinosomes contact mitochondria, enabling albumin translocation into the mitochondrial intermembrane space where it interacts with DHODH, diminishing inhibitor binding and restoring DHODH activity. This adaptive response contributes to drug resistance in vitro and in vivo, and co-administration of DHODH inhibitors with macropinocytosis blockers or EGFR inhibitors enhances anti-tumor efficacy. Our findings reveal a previously unknown metabolic stress-induced macropinocytosis pathway and provide a rationale for combination therapy to enhance DHODH inhibitor efficacy in cancer treatment. DHODH inhibition triggers TERF2IP lactylation, unmasking its moonlighting transcription of epiregulin to drive EGFR-dependent macropinocytosis; macropinosome–mitochondria contact routes albumin onto DHODH, a resistance axis reversed by EGFR blockade.
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