Nature communicationsSep 14, 2026

Blocking DHODH may cause albumin-related drug resistance by activating cell intake and energy center interactions through TERF2IP lactylation

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Sep 16, 2026

Abstract

Inhibition of dihydroorotate dehydrogenase (DHODH) is associated with the induction of macropinocytosis in cancer cells.

Macropinocytosis allows cancer cells to scavenge nutrients, which may contribute to tumor progression and chemoresistance.
DHODH inhibition triggers a metabolic shift toward glycolysis and leads to lactate accumulation.
This metabolic reprogramming promotes the lactylation of a protein involved in gene activation, influencing macropinocytosis.
Macropinosomes formed during this process contact mitochondria, facilitating the transport of albumin and restoring DHODH activity.
This adaptive response can contribute to drug resistance both in laboratory settings and in living organisms.
Combining DHODH inhibitors with macropinocytosis blockers or EGFR inhibitors may enhance the effectiveness of cancer treatments.

Simplified

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.

Full Text

Full text is available at the source.

View Full Text ↗

Blocking DHODH may cause albumin-related drug resistance by activating cell intake and energy center interactions through TERF2IP lactylation

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the crispr gene editing brief