Evidence map›Paper›PMID 40287668›Full record

ArticleCell communication and signaling : CCS2025

ER-phagy mediates the anti-tumoral synergism between HDAC inhibition and chemotherapy.

Felix J Gössl, Pierfrancesco Polo, Frederik Helmprobst, André Menzenbach, Alexander Visekruna, Thomas M Gress, Till Adhikary, Matthias Lauth

Abstract read
In one paragraph

Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Felix J GösslClinic of Gastroenterology, Endocrinology and Metabolism, Center for Tumor- and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
Pierfrancesco PoloClinic of Gastroenterology, Endocrinology and Metabolism, Center for Tumor- and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
Frederik HelmprobstCore Facility for Mouse Pathology and Electron Microscopy, Philipps University Marburg, Marburg, 35043, Germany.
André MenzenbachClinic of Gastroenterology, Endocrinology and Metabolism, Center for Tumor- and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
Alexander VisekrunaInstitute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, 35043, Germany.
Thomas M GressClinic of Gastroenterology, Endocrinology and Metabolism, Center for Tumor- and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
Till AdhikaryCenter for Tumor- and Immune Biology, Institute for Biomedical Informatics and Biostatistics, Philipps University Marburg, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
Matthias LauthClinic of Gastroenterology, Endocrinology and Metabolism, Center for Tumor- and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, Marburg, 35043, Germany. lauth@staff.uni-marburg.de.

Funding

Deutsche Forschungsgemeinschaft KFO325
6 · The paper itself

Abstract

backgroundHistone deacetylase inhibitors (HDACi) are clinically approved drugs for the treatment of hematological malignancies synergizing with chemotherapy. However, despite the long history of HDACi, the mechanistic underpinnings of this synergism have remained unclear.

methodsUsing transmission electron microscopy, we identified autophagy and ER-stress in HDACi-treated cells. We quantified ER-phagy and ER-stress with reporter systems by using 3D-deconvolution microscopy and flow cytometry. We complemented these data with qPCR and Western blot results. Apoptosis rates were assessed using a caspase assay and flow cytometry, and large public datasets were utilized.

resultsHDAC blockade results in specific upregulation of the selective autophagy receptor FAM134B (RETREG1) and the induction of ER-phagy. Combined with the chemotherapeutic drug Gemcitabine, this results in subsequent elevated ER-stress levels and apoptosis. Inhibiting the distinct ER-stress branches fully rescues this process. Broadening the scope of these findings, certain non-HDAC-inhibitory and clinically approved compounds like Loperamide and Nelfinavir are able to induce FAM134B and could hence constitute novel Gemcitabine-synergizing molecules. Additionally, pancreatic cancer patients with high FAM134B expression have significantly longer survival rates under chemotherapy.

conclusionIn summary, we provide mechanistic evidence for ER-phagy playing a hitherto unknown central role in the clinical synergy between HDACi and chemotherapy.

Indexed as

Antineoplastic AgentsAutophagyEndoplasmic ReticulumHistone Deacetylase InhibitorsApoptosisCell Line, TumorDeoxycytidineDrug SynergismEndoplasmic Reticulum StressGemcitabineHumansPancreatic NeoplasmsAntineoplastic AgentsDeoxycytidineGemcitabineHistone Deacetylase InhibitorsChemotherapyER-phagyER-stressFAM134BGemcitabineHDAC inhibitorsPancreatic cancerRETREG1

Identifiers

PMID40287668
PMCPMC12034116

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.