Enzyme USP16 Drives Pancreatic Cancer Growth and Gemcitabine Resistance Through a Glycolytic Switch

Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies in human medicine, a disease whose aggressive biology and stubborn resistance to chemotherapy have frustrated oncologists for decades. Gemcitabine, a nucleoside analog that has anchored first-line treatment regimens for years, frequently delivers disappointing results because tumors either resist the drug from the outset or acquire resistance during therapy. Now, a study published in Cellular and Molecular Life Sciences has uncovered a molecular pathway that helps explain why. A research team led by investigators at Jilin University, Harbin Medical University, Fujian Medical University and Central South University identified the enzyme ubiquitin-specific peptidase 16, or USP16, as a central driver of both tumor progression and gemcitabine resistance, operating through a cascade that rewires how pancreatic cancer cells generate energy.

USP16 belongs to a large family of deubiquitinating enzymes, proteases that snip ubiquitin tags off target proteins. Ubiquitination is one of the cell’s principal mechanisms for marking proteins for destruction: when chains of ubiquitin molecules, particularly those linked through their lysine 48 residues, are attached to a protein, the proteasome recognizes the tag and degrades the cargo. Deubiquitinases reverse this process, rescuing proteins from degradation and thereby fine-tuning their abundance. In the new study, the researchers found that USP16 is markedly upregulated in gemcitabine-resistant pancreatic cancer specimens, and that elevated levels of the enzyme correlate with metastatic disease and poor patient prognosis, positioning USP16 as a potential biomarker of aggressive disease.

The functional experiments carried out by the team went beyond correlation. When the researchers silenced USP16 genetically or inhibited it pharmacologically, pancreatic cancer cells lost key malignant behaviors: proliferation slowed, invasive capacity diminished, and, critically, sensitivity to gemcitabine was restored. The same effects were reproduced in animal models, where USP16 suppression curbed tumor progression and re-sensitized tumors to chemotherapy. These results, the authors report, held both in vitro and in vivo, suggesting that USP16 is not merely a passenger mutation or a passive marker of aggressive disease but an active participant in maintaining the resistant phenotype.

The mechanistic heart of the paper lies in metabolism. Cancer cells famously favor glycolysis, the fermentation of glucose into lactate, even in the presence of abundant oxygen, a phenomenon known as the Warburg effect. This metabolic reprogramming supplies rapidly dividing tumors with biosynthetic building blocks and helps them survive environmental stress. The researchers demonstrated that USP16 promotes this glycolytic switch by stabilizing a transcription factor called Far Upstream Element Binding Protein 1, or FUBP1. Biochemical analysis showed that USP16 preferentially removes K48-linked polyubiquitin chains from FUBP1, shielding the protein from proteasomal destruction. With FUBP1 stabilized, pancreatic cancer cells accumulate higher levels of this transcription factor in the nucleus.

FUBP1, in turn, drives transcription of lactate dehydrogenase A, or LDHA, the enzyme that catalyzes the conversion of pyruvate to lactate, the final and defining step of anaerobic glycolysis. By enhancing FUBP1-dependent LDHA expression, USP16 effectively turns up the dial on lactate production, fueling the metabolic state that supports rapid proliferation and chemoresistance. The connection is biologically plausible: high glycolytic flux has been repeatedly linked to drug resistance in solid tumors, partly because glycolytic tumors maintain acidic, hypoxic microenvironments that blunt the efficacy of chemotherapeutic agents and promote survival signaling. The USP16-FUBP1-LDHA axis therefore offers a coherent explanation for how a single deubiquitinase can simultaneously promote metastatic behavior and undermine gemcitabine therapy.

Perhaps the most intricate portion of the study concerns how USP16 itself becomes overexpressed in pancreatic cancer in the first place. The researchers traced the excess USP16 to two upstream layers of regulation. The first involves N6-methyladenosine, or m6A, the most abundant internal chemical modification in messenger RNA. The methyltransferase-like 3 enzyme, METTL3, installs m6A marks on the USP16 transcript, and these modifications enhance the message’s translation or processing. The second layer involves Insulin-like Growth Factor 2 mRNA-Binding Protein 1, or IGF2BP1, a reader protein that recognizes m6A-modified transcripts and stabilizes them, preventing degradation. Together, METTL3-mediated methylation and IGF2BP1-dependent stabilization elevate USP16 protein levels in pancreatic cancer cells, setting the entire pathological cascade in motion.

This architecture, which the authors describe as a METTL3/IGF2BP1-USP16-FUBP1-LDHA regulatory axis, is notable because it links three major themes in contemporary cancer biology: epitranscriptomic regulation through RNA modifications, post-translational control through ubiquitination, and metabolic reprogramming through glycolysis. Each layer of the axis represents a potential point of therapeutic intervention, and the study’s demonstration that both genetic and pharmacological USP16 inhibition suppress tumor progression suggests that deubiquitinase inhibitors could form the basis of new combination strategies designed to be administered alongside gemcitabine.

The clinical implications are considerable. Gemcitabine resistance is one of the chief reasons pancreatic cancer has a five-year survival rate that remains among the lowest of any major cancer. If USP16 levels can be measured reliably in tumor biopsies, the enzyme could serve as a biomarker identifying patients likely to derive limited benefit from gemcitabine-based regimens, guiding clinicians toward alternative or intensified approaches. More ambitiously, if USP16 inhibitors can be developed with acceptable safety profiles, they might resensitize resistant tumors to existing chemotherapy, extending the usefulness of a drug that has been a workhorse in pancreatic oncology for decades. The study’s finding that pharmacological USP16 inhibition restored gemcitabine sensitivity in vivo provides an early proof of concept for that strategy.

Caveats remain, as they do with any preclinical study. The work was conducted in cell lines and animal models, and the translation of deubiquitinase inhibition into human therapy will require medicinal chemistry advances, since deubiquitinases share catalytic mechanisms that can make selective inhibition challenging. The authors also note that the published version is an early-release, peer-reviewed accepted manuscript subject to further editorial refinement. Nonetheless, the identification of a complete signaling axis, from RNA modification through protein stabilization to metabolic enzyme expression, gives researchers a detailed map of a resistance pathway that had remained poorly understood, and it adds USP16 to the growing list of deubiquitinating enzymes implicated in cancer metabolism.

For a disease that has seen painfully slow therapeutic progress, studies that illuminate the machinery of chemoresistance carry real weight. By showing how an m6A-modified, IGF2BP1-stabilized transcript elevates a deubiquitinase that in turn protects a transcription factor governing lactate metabolism, the research team has connected molecular layers that are usually studied in isolation. Whether targeting USP16 will ultimately improve outcomes for patients with pancreatic ductal adenocarcinoma will depend on the development of clinically viable inhibitors and appropriately designed trials, but the study establishes a clear, testable framework for attacking gemcitabine resistance at its metabolic roots, and it underscores how deeply the survival of this formidable cancer depends on the reprogramming of its energy economy.

Subject of Research: USP16-mediated glycolytic reprogramming and gemcitabine resistance in pancreatic ductal adenocarcinoma

Article Title: USP16 promotes pancreatic ductal adenocarcinoma progression and gemcitabine resistance through FUBP1/LDHA axis-mediated glycolysis

Article References: Dong, Y., Lin, C., Fang, H., Tan, Z., Lu, J., Liu, Z., Lai, S., & Wang, Y. (2026). USP16 promotes pancreatic ductal adenocarcinoma progression and gemcitabine resistance through FUBP1/LDHA axis-mediated glycolysis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06466-w

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06466-w

Keywords: pancreatic ductal adenocarcinoma, USP16, deubiquitinase, FUBP1, LDHA, glycolysis, gemcitabine resistance, m6A modification, METTL3, IGF2BP1, cancer metabolism, chemoresistance