2. Academic Validation
  3. 4-Phenylbutyrate attenuates doxorubicin-induced cardiorenal comorbidity by suppressing ER stress-mediated epithelial-mesenchymal transition and endothelial-mesenchymal transition

4-Phenylbutyrate attenuates doxorubicin-induced cardiorenal comorbidity by suppressing ER stress-mediated epithelial-mesenchymal transition and endothelial-mesenchymal transition

  • Eur J Pharmacol. 2026 Feb 15:1015:178580. doi: 10.1016/j.ejphar.2026.178580.
Wenyu Hui 1,  Weiwei Cui 1,  Jie Li 1,  Mengyuan Cheng 1,  Yangyang Liu 1,  Yunru Peng 2,  Yongfang Ding 3
Affiliations

Affiliations

  • 1 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
  • 2 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China. Electronic address: [email protected].
  • 3 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China. Electronic address: [email protected].
PMID: 41571078 DOI: 10.1016/j.ejphar.2026.178580
Abstract

Objective: Cardiorenal syndrome (CRS), a spectrum of disorders involving intertwined cardiac and renal dysfunction, poses a significant challenge to mechanistic research due to a lack of accurate in vivo models. This study investigated the role of endoplasmic reticulum (ER) stress in mediating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transition (EMT) in a mouse model of cardiorenal comorbidity. Moreover, we investigated the therapeutic potential of 4-phenylbutyrate (4-PBA), an ER stress inhibitor, in attenuating cardiorenal comorbidity.

Methods: We employed a doxorubicin (Dox)-induced mouse model of cardiorenal comorbidity to investigate the role of ER stress in mediating EndMT and EMT. Six weeks post-Dox treatment, echocardiography, urinalysis, and blood tests were performed, complemented by immunofluorescence and Western blot analyses of cardiac and renal tissues. 4-PBA was intraperitoneally administered to evaluate the effect of ER stress inhibition on cardiorenal comorbidity.

Results: Dox administration significantly impaired cardiac and renal function, accompanied by pronounced fibrosis and upregulation of EndMT, EMT and ER stress markers. 4-PBA treatment attenuated cardiac injury, restored function, and ameliorated renal lesions. Consistent with in vivo results, Dox activated ER stress in HUVEC and HK-2 cells, promoting mesenchymal transformation. Critically, 4-PBA suppressed EndMT and EMT in vitro, supporting ER stress involvement in these processes.

Conclusions: Our findings demonstrate that Dox induces concurrent cardiorenal dysfunction, primarily through ER stress-mediated EndMT and EMT transitions. Importantly, pharmacological inhibition of ER stress with 4-PBA attenuated these pathological changes, suggesting its potential as a therapeutic strategy for cardiorenal syndrome.

Keywords

4-phenylbutyrate; Cardiorenal comorbidity; EMT; EndMT; Endoplasmic reticulum stress.

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