Histone deacetylase 6: A new player in oxidative stress-associated disorders and cancers - Review

Sep 23, 2026

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Histone deacetylase 6 (HDAC6) regulates cellular responses to oxidative stress, acting uniquely among histone deacetylases by primarily deacetylating non-histone proteins. This review consolidates findings on how HDAC6 shapes oxidative-stress pathways and influences diseases including neurodegeneration, cancer, and cardiovascular disorders. Preclinical evidence indicates that HDAC6 inhibition may alleviate symptoms and modify disease progression across multiple disease models. By clarifying HDAC6’s multifaceted roles, the review highlights its value as a therapeutic target and supports new treatment strategies for oxidative stress-related illnesses.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

HDAC6: An overview

Function of HDAC6 in oxidative stress-related disease

HDAC6 and cancer

HDAC6 is a potential therapeutic target for disease

Challenges and limitations in HDAC6 inhibitor research

Conclusion and future perspectives

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 56: 137, 2025 Histone deacetylase 6: A new player in oxidative stress‑associated disorders and cancers (Review) FEI QU 1 , QINGQING ZHAO 1 and YI JIN2 1Department of Pathology, Central Hospital Affiliated to Shandong First Medical University, 2 Jinan, Shandong 250013, P.R. China; Metabolism and Disease Research Centre, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, P.R. China Received March 20, 2025; Accepted June 16, 2025 DOI: 10.3892/ijmm.2025.5578 Abstract. Histone deacetylase 6 (HDAC6), a distinctive member of the histone deacetylase family, plays a crucial role in regulating the cellular response to oxidative stress. Unlike other HDACs, HDAC6 primarily deacetylates non‑histone proteins, influencing various cellular functions critical to the pathogenesis of numerous oxidative stress‑related diseases. This review summarizes the latest research on how HDAC6 affects oxidative stress pathways and its impact on diseases such as neurodegeneration, cancer and cardiovascular disorders. Additionally, the therapeutic potential of targeting HDAC6, as evidenced by preclinical trials, was discussed, suggesting that HDAC6 inhibitors can ameliorate symptoms and alter disease progression in numerous disease models. By elucidating the multifaceted roles of HDAC6 in oxidative stress and disease, the review aims to underscore its potential as a therapeutic target. This review enhances the understanding of HDAC6 and presents new opportunities for innovative treatment approaches that can address oxidative stress‑related illnesses. Contents 1. Introduction 2. HDAC6: An overview 3. Function of HDAC6 in oxidative stress‑related disease 4. HDAC6 and cancer 5. HDAC6 is a potential therapeutic target for disease 6. Challenges and limitations in HDAC6 inhibitor research 7. Conclusion and future perspectives Correspondence to: Professor Yi Jin, Metabolism and Disease Research Centre, Central Hospital Affiliated to Shandong First Medical University, 105 Jiefang Road, Jinan, Shandong 250013, P.R. China E‑mail: [jinhongyi@mail.hzau.edu.cn](jinhongyi@mail.hzau.edu.cn) Key words: HDAC6, aggresome‑autophagy pathway, reactive oxygen species, protein homeostasis 1. Introduction The development of numerous long‑term illnesses is caused by oxidative stress, which occurs when the body cannot effectively neutralize the damaging effects of reactive oxygen species (ROS) due to an imbalance in production and detoxi‑ fication processes (1) . This lack of balance results in cellular damage, contributing to the development of various illnesses, such as neurodegenerative diseases, cancer, heart diseases and metabolic disorders (2‑5) . The cellular response to oxidative stress involves a complex network of signaling pathways that orchestrate defense mechanisms, repair processes and at times cell death (6). Among the myriad regulators of these pathways, histone deacetylase 6 (HDAC6) emerges as a pivotal player due to its unique functions and substrates. HDAC6, part of the class IIb HDAC group, is mainly found in the cytoplasm and has distinct characteristics that set it apart from other HDACs, which mainly reside in the nucleus and control gene expres‑ sion through histone deacetylation (7) . HDAC6 is known for removing acetyl groups from non‑histone proteins such as α‑tubulin, cortactin and heat shock protein 90 (HSP90), which play vital roles in preserving cell structure, move‑ ment and response to stress (8‑10) . Through its influence on these substrates, HDAC6 directly impacts cellular dynamics, signaling pathways and survival mechanisms under oxidative stress conditions. The role of HDAC6 in oxidative stress is paradoxical and multifaceted. On the one hand, HDAC6 promotes cellular survival by maintaining the dynamic stability of the cytoskel‑ eton through the deacetylation of α‑tubulin (11) . This action facilitates the proper assembly of

FAQs

What is the main function of HDAC6 in oxidative stress responses?

HDAC6 regulates cellular responses to oxidative stress by deacetylating non-histone proteins, thereby influencing multiple cellular processes relevant to oxidative stress-related disease.

How does HDAC6 influence diseases such as neurodegeneration and cancer?

In neurodegenerative disorders, HDAC6 activity is linked to excessive acetylation and accumulation of improperly folded proteins, while in cancer HDAC6 affects malignancy through regulation of oncogenic and tumor-suppressor acetylation, influencing migration, invasion, and chemoresistance.

Why are HDAC6 inhibitors considered a potential therapeutic strategy?

Preclinical trials suggest HDAC6 inhibitors can ameliorate symptoms and alter disease progression in multiple disease models, supporting HDAC6 as a therapeutic target for oxidative stress-related illnesses.

Sep 23, 2026

Uploaded by Đào