Thyroid cancer is the most commonly occurring endocrine malignancy and its incidence has increased steadily over the past three decades worldwide [
1,
2]. Generally, thyroid cancer can be treated effectively with surgery or radioactive iodine [
3]. ATC is the least common, but the most aggressive, of all thyroid cancers [
4]. The mechanisms driving the progress of ATC are not completely understood. ATCs are currently treated with chemotherapy, radiotherapy, and/or surgery [
4,
5]. Nevertheless, patients with ATC only have a median survival of 5 months and less than 20 % survive for 1 year after diagnosis [
6]. Early tumor dissemination occurs in this type of cancer, resulting in 40 % of patients showing distant metastases and 90 % showing invasion of adjoining tissue on presentation [
7]. The present study investigated HDAC inhibitors as a novel chemotherapy for PTC and ATC. HDACs are often highly expressed in cancer cells [
8‐
10]. These enzymes restrain the transcription of tumor suppressor genes and so offer bright targets for cancer therapy [
11,
12]. HDAC inhibitors are a group of small molecules that accelerate gene transcription by reducing HDAC activity, inducing chromatin remodeling; these inhibitors have been extensively studied as potential drugs for treating cancer [
12‐
15]. HDAC inhibitors affect various well-known features of cancer cells, involving apoptosis, autophagy, growth inhibition and differentiation [
16‐
18]. They are extremely specific for cancer cells over normal cells, owing to their induction of pro-apoptotic genes and ER stress, in addition to their effects on DNA repair mechanisms [
19,
20]. HNHA is a dominant HDAC inhibitor that was previously shown to drive histone acetylation and downregulate the expression of HDAC target genes [
21,
22]. HNHA showed powerful anti-cancer activity in breast cancer cells and fibrosarcoma [
21‐
23]. Here, we researched this dominant HDAC inhibitor and its ER stress-mediated roles in thyroid cancer and explored the effects of HNHA on apoptotic cell death pathways in PTC and ATC.