Chidamide enhances the sensitivity of gastric cancer to 5-fluorouracil chemotherapy by suppressing the HDAC3/HNF4A/TYMS axis

Sep 30, 2026

Chidamide increases the sensitivity of gastric cancer cells to 5-fluorouracil (5-FU) by suppressing the HDAC3/HNF4A/TYMS axis. Gastric cancer frequently acquires resistance to 5-FU, with progression commonly occurring within 0–8 months, making resistance mechanisms critical for improving outcomes. Using RT-qPCR, Western blot, IF, and IHC, along with CCK-8 and colony formation assays, the study links chidamide to reduced TYMS and HDAC3 and to enhanced acetylation of HNF4A at lysine 458, decreasing HNF4A phosphorylation at serine 313.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

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Introduction

Gastric cancer burden and 5-FU resistance

Rationale for chidamide and HDAC targeting

Mechanistic basis of 5-FU and TYMS as a target

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN Chidamide enhances the sensitivity of gastric cancer to 5-ﬂuorouracil chemotherapy by suppressing the HDAC3/ HNF4A/TYMS axis Xiaofei Zhang 1,3, Lei Shi2,3, Yaping Gao 1, Chenyi Zhou1, Xiyin Wang1 and Xiaonan Shi 1 ✉ © The Author(s) 2025 | | | | | --- | --- | --- | | | Gastric cancer (GC) is among the most common malignant tumors in China and leads in incidence across all cancer types. For over three decades, the standard treatment has been traditional chemotherapy, which often involves monotherapy with 5-ﬂuorouracil (5-FU) or its combination with other drugs. Unfortunately, nearly all cases of GC eventually develop resistance to 5-FU, typically displaying a median time to progression that ranges from 0 to 8 months. Therefore, elucidating the mechanisms of acquired resistance to 5-FU in GC continues to be a critical focus of ongoing research. Various gene and protein expression analyses were conducted utilizing techniques such as RT-qPCR, Western blot, IF, and IHC staining. Cell viability and proliferation were assessed using the CCK-8 assays and colony formation assays, respectively. Interactions among HDAC3, HNF4A, and TYMS were explored using ChIP, Co-IP, and dual-luciferase reporter assays. Chidamide increased the sensitivity of GC cells to 5-FU through the downregulation of TYMS and HDAC3 . Additionally, the treatment with chidamide led to increased acetylation of HNF4A at lysine 458, due to the suppression of HDAC3, which in turn decreased phosphorylation of HNF4A at serine 313 . Chidamide promoted the sensitivity of GC to 5-FU by suppressing the HDAC3/HNF4A/TYMS axis. This research may provide a foundation for using chidamide | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | to counteract resistance to 5-FU in GC. | | | | | Cell Death and Disease (2026)17:2; [https://doi.org/10.1038/s41419-025-08247-y](https://doi.org/10.1038/s41419-025-08247-y) | | | | | | INTRODUCTION Gastric cancer (GC) ranks as one of the most prevalent malignant tumors in China, leading in incidence among all cancer types [1] . Annually, it accounts for approximately 783,000 deaths, nearly a quarter of all cancer fatalities [2] . Traditional chemotherapy, particularly monotherapy with 5-ﬂuorouracil (5-FU) or its combination with other drugs, has been used as the standard treatment for over three decades [3] . Despite these efforts, the prognosis for patients with advanced GC remains dismal, with median overall survival rates barely exceeding one year [4]. Many patients initially respond to 5-FU but eventually relapse as their tumors develop resistance, leading to progression and death [4] . This resistance highlights the need for understanding the underlying mechanisms of tumor cell survival post-chemotherapy, a critical area of ongoing research. Chidamide is the ﬁrst orally available, subtype-selective histone deacetylase (HDAC) inhibitor approved in China [5]. It has shown a synergistic antitumor effect when combined with 5-FU in other cancers, such as colon [6]. However, the speciﬁc impact of chidamide on 5-FU resistance in GC treatment remains unexplored. 5-FU, structurally similar to thymine, is metabolized into ﬂuorodeoxyuridine monophosphate (FdUMP) and ﬂuorouridine triphosphate (FUTP) to exert its therapeutic effects [7] . FdUMP forms a crucial covalent complex with thymidylate synthase (TYMS) and 5,10-methylenetetrahydrofolate, further inhibiting TYMS and disrupting DNA synthesis [8] . Additionally, themisincorporation of FUTP during RNA synthesis impairs RNA function and hinders tumor cell proliferation [9] . This mechanism is essential for 5-FU’s cytotoxic and antitumor effects [9] . Preliminary research analyzing TYMS expression in GC using the TCGA database revealed high levels of TYMS expression in GC, highlighting its potential as a therapeutic target to enhance the efﬁcacy of 5-FU

FAQs

Why is 5-FU resistance in gastric cancer a major research focus?

Nearly all gastric cancer cases eventually develop resistance to 5-FU, leading to tumor progression and death. The median time to progression ranges from 0 to 8 months, underscoring the need to understand the underlying mechanisms.

What is the proposed role of chidamide in improving 5-FU response?

Chidamide enhances gastric cancer sensitivity to 5-FU by downregulating TYMS and HDAC3. It suppresses the HDAC3/HNF4A/TYMS axis, affecting downstream post-translational regulation of HNF4A.

How does chidamide alter HNF4A signaling in the context of 5-FU treatment?

Chidamide increases acetylation of HNF4A at lysine 458 by suppressing HDAC3. This leads to decreased phosphorylation of HNF4A at serine 313, supporting improved 5-FU sensitivity.

Sep 30, 2026

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