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  3. 20-Deoxyingenol attenuated doxorubicin-induced cardiotoxicity by promoting autolysosome degradation through the UCHL3-TFEB pathway

20-Deoxyingenol attenuated doxorubicin-induced cardiotoxicity by promoting autolysosome degradation through the UCHL3-TFEB pathway

  • Phytomedicine. 2025 Nov:147:157220. doi: 10.1016/j.phymed.2025.157220.
De-Shu Chen 1,  Yu-Xi Wang 1,  Miao-Yuan Liang 1,  Dong-Dong Que 1,  Jing Shao 2,  Chong-Bin Zhong 1,  Ya-Shu Yang 1,  Bo-Wen Rui 1,  Guan-Lin Huang 1,  Zhen-Yu Zhuang 1,  Jun-Jie Guan 1,  Xiang-Zhou Chen 1,  Hong-Wei Mo 1,  Jing Yan 1,  Miao-Miao Ma 3,  Wen-Jie Yu 4,  Ping-Zhen Yang 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, Guangdong, China.
  • 2 Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 3 Department of Gastroenterology, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine (Nanhai District Hospital of Traditional Chinese Medicine of Foshan City), Foshan, China. Electronic address: 3216704801@qq.com.
  • 4 Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, Guangdong, China. Electronic address: 846629261@qq.com.
  • 5 Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, Guangdong, China. Electronic address: y_pingzhen@126.com.
PMID: 40916238 DOI: 10.1016/j.phymed.2025.157220
Abstract

Background: Impaired autophagic flux is an essential contributor to doxorubicin (DOX)-induced cardiotoxicity (DIC). TFEB is recognized as a key regulator of DOX-induced autolysosome accumulation; however, the mechanisms by which DOX suppresses TFEB expression remain unclear. 20-Deoxyingenol (20-DOI) is a small-molecule compound whose potential protective effects against DIC has not yet been elucidated.

Purpose: We investigated the therapeutic potential and molecular mechanism of 20-DOI in protecting against DIC.

Methods: Acute DIC was induced in mice by a single DOX dose (15 mg/kg). Echocardiography, myocardial injury biomarkers, and atrophy-related parameters were assessed to evaluate cardiotoxicity in vivo. Propidium iodide (PI) and cardiac troponin T (cTnT) staining were used to assess cell death and atrophy in vitro. Autophagic markers, LysoSensor, and mRFP-GFP-LC3 puncta were used to monitor autophagic flux. RNA Sequencing (RNA-seq) analysis and co-immunoprecipitation (Co-IP) were performed to validate the underlying molecular mechanisms.

Results: 20-DOI mitigated cardiac dysfunction, myocardial injury, and atrophy both in vivo and in vitro. Moreover, 20-DOI enhanced lysosomal activity and facilitated autolysosome degradation, thereby restoring the autophagic flux impaired by DOX. Inhibition of autophagic flux with chloroquine (CQ) or bafilomycin A1 (BafA1) abolished the protective effects of 20-DOI against DIC. Mechanistically, 20-DOI rescued DOX-induced downregulation of TFEB without affecting its nuclear translocation. Silencing TFEB with siRNA reduced the protective effects of 20-DOI on autophagic flux, cardiomyocyte death, and myocardial atrophy. Finally, we demonstrated for the first time that 20-DOI rescues DOX-induced TFEB downregulation via UCHL3-mediated deubiquitination of TFEB.

Conclusion: Collectively, our findings indicate that 20-DOI mitigates DIC by promoting autolysosome clearance through activation of the UCHL3-TFEB axis. Thus, 20-DOI may represent a promising therapeutic agent for preventing DIC.

Keywords

20-Deoxyingenol; Autolysosome; Doxorubicin-induced cardiotoxicity; Transcription factor EB; Ubiquitin carboxyl terminal hydrolase L3.

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