Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of total heart failure patients and is characterized by peripheral circulation, cardiac remodelling and comorbidities (such as advanced age, obesity, hypertension and diabetes) with limited treatment options. Chidamide (HBI‐8000) is a domestically produced benzamide‐based histone deacetylase isoform‐selective inhibitor used for the treatment of relapsed refractory peripheral T‐cell lymphomas. Based on our in vivo studies, we propose that HBI‐8000 exerts its therapeutic effects by inhibiting myocardial fibrosis and myocardial hypertrophy in HFpEF patients. At the cellular level, we found that HBI‐8000 inhibits AngII‐induced proliferation and activation of CFs and downregulates the expression of fibrosis‐related factors. In addition, we observed that the HFpEF group and AngII stimulation significantly increased the expression of TGF‐β1 as well as phosphorylated p38MAPK, JNK and ERK, whereas the expression of the above factors was significantly reduced after HBI‐8000 treatment. Activation of the TGF‐β1/MAPK pathway promotes the development of fibrotic remodelling, and pretreatment with SB203580 (p38MAPK inhibitor) reverses this pathological change. In conclusion, our data suggest that HBI‐8000 inhibits fibrosis by modulating the TGF‐β1/MAPK pathway thereby improving HFpEF. Therefore, HBI‐8000 may become a new hope for the treatment of HFpEF patients.

中文翻译：

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HBI-8000 通过 TGF-β1/MAPK 信号通路改善心力衰竭并保留射血分数

射血分数保留的心力衰竭（HFpEF）约占心力衰竭患者总数的 50%，其特点是外周循环、心脏重塑和合并症（如高龄、肥胖、高血压和糖尿病），治疗选择有限。西达本胺（HBI-8000）是一种国产苯甲酰胺类组蛋白脱乙酰酶异构体选择性抑制剂，用于治疗复发难治性外周T细胞淋巴瘤。基于我们的体内研究，我们提出HBI-8000通过抑制HFpEF患者的心肌纤维化和心肌肥厚来发挥治疗作用。在细胞水平上，我们发现 HBI-8000 抑制 AngII 诱导的 CF 增殖和活化，并下调纤维化相关因子的表达。此外，我们观察到HFpEF组和AngII刺激显着增加了TGF-β1以及磷酸化p38MAPK、JNK和ERK的表达，而HBI-8000处理后上述因子的表达显着降低。 TGF-β1/MAPK 通路的激活促进纤维化重塑的发展，而用 SB203580（p38MAPK 抑制剂）预处理可逆转这种病理变化。总之，我们的数据表明 HBI-8000 通过调节 TGF-β1/MAPK 通路抑制纤维化，从而改善 HFpEF。因此，HBI-8000可能成为治疗HFpEF患者的新希望。