2. Academic Validation
  3. Dimethyl fumarate abrogates hepatocellular carcinoma growth by inhibiting Nrf2/Bcl-xL axis and enhances sorafenib's efficacy

Dimethyl fumarate abrogates hepatocellular carcinoma growth by inhibiting Nrf2/Bcl-xL axis and enhances sorafenib's efficacy

  • Sci Rep. 2025 May 14;15(1):16724. doi: 10.1038/s41598-025-00832-7.
Oluwasijibomi Damola Faleti # 1 2 3,  Moyed Alsaadawe # 2 4,  Jingyi Long # 1 2,  Qingshuang Luo # 1 2,  Longtai Hu 1 2,  Yuanbin Zhang 1 2,  Simin Deng 1,  Gongfa Wu 5,  Weiyi Fang 6,  Mingliang He 7 8,  Xiaoming Lyu 9 10
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China.
  • 2 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China.
  • 3 Department of Biomedical Sciences, City University of Hong Kong, HKSAR, Kowloon, 999077, China.
  • 4 Cancer Center, TCM-Integrated Hospital, Southern Medical University, Guangzhou, 510630, China.
  • 5 Department of Pathology, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511300, Guangdong, China.
  • 6 Cancer Center, TCM-Integrated Hospital, Southern Medical University, Guangzhou, 510630, China. minglihe@cityu.edu.hk.
  • 7 Department of Biomedical Sciences, City University of Hong Kong, HKSAR, Kowloon, 999077, China. minglihe@cityu.edu.hk.
  • 8 Biotechology Center, CityU Shenzhen Research Institute, Nanshan, Shenzhen, 518000, China. minglihe@cityu.edu.hk.
  • 9 Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China. xiaomlyu@smu.edu.cn.
  • 10 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China. xiaomlyu@smu.edu.cn.
  • # Contributed equally.
PMID: 40369009 DOI: 10.1038/s41598-025-00832-7
Abstract

Hepatocellular carcinoma (HCC) is characterized by poor prognosis and remains a leading cause of Cancer mortality worldwide. Advanced HCC is managed with several first-line therapies, including tyrosine kinase inhibitors (TKI) and immunotherapy (mAb-PD-1 and mAb-VEGF). However, the efficacy of HCC therapeutics is often short-lived. Recent studies have demonstrated that the activation of the Nrf2-Bcl-xL pathway contributes to poor prognosis in a subset of HCC patients. Here, we found that dimethyl fumarate (DMF), a drug used for treating psoriasis and multiple sclerosis, regulates the Nrf2-Bcl-xL signaling axis to inhibit HCC growth in a mice xenograft model. Mechanistically, the downregulation of the Nrf2-Bcl-xL axis led to mitochondria stress and Apoptosis in vitro and in vivo. Enforced Nrf2 or Bcl-xL expression in HCC cells markedly reversed the antitumor effects of DMF in HCC cells. Importantly, DMF enhanced sorafenib's antitumor effects. Collectively, our results demonstrate new mechanism insights into the antitumor effects of DMF and that Nrf2-targeted therapy might improve HCC treatment outcomes.

Keywords

B-cell lymphoma-extra large (Bcl-xL); Chemoresistance; Dimethyl fumarate; Hepatocellular carcinoma.

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