ARHGAP21 enhances metastasis in hepatocellular carcinoma by inhibiting ubiquitination of filamin A

  • Cell Death Discov. 2026 Apr 9;12(1):240. doi: 10.1038/s41420-026-03103-0.
Huijun Yao  1 ,  Ziping Xie  2 ,  Xingyu Tao  1 ,  Xingyi Zhong  3 ,  Xiaoxiao Wang  1 ,  Kaiwen Xi  1 ,  Zhiqin Zhu  4 ,  Yangfeng Zhang  5 ,  Feiye Liu  6 ,  Junhao Lin  7 ,  Fengsheng Chen  8
Affiliations
  • 1. Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, China.
  • 2. Xiamen Branch, Zhongshan hospital, Fudan University, Shanghai, China.
  • 3. Department of Clinical Research, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • 4. Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China.
  • 5. Department of Medical Oncology, The People's Hospital of Hezhou, Hezhou City, China.
  • 6. Oncology Center, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China. [email protected].
  • 7. Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, China. [email protected].
  • 8. Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, China. [email protected].
PMID: 41957357 DOI: 10.1038/s41420-026-03103-0
Abstract

Rho GTPase-activating protein 21 (ARHGAP21) plays a role in the occurrence and development of certain cancers, but its function in hepatocellular carcinoma (HCC) remains unclear. In this study, elevated ARHGAP21 expression was observed in both HCC cell lines and tissues and correlated with poor patient prognosis. Knockdown of ARHGAP21 suppressed HCC cell migration and invasion in vitro by regulating the actin Cytoskeleton, while overexpression of ARHGAP21 had the opposite effect. In vivo, knockdown of ARHGAP21 inhibited HCC tumorigenesis and metastasis. Mechanistically, we demonstrated that ARHGAP21 directly binds to FLNA, and the PDZ domain of ARHGAP21 functions as a potential mediator of its binding to the 1-1200 aa fragment of FLNA. ARHGAP21 also directly binds to and recruits HSP90α to stabilize FLNA by inhibiting its ubiquitination and degradation. Overexpression of FLNA reversed the Cytoskeleton remodeling-related suppression of tumor metastasis in ARHGAP21-knockdown HCC cells. These results revealed that ARHGAP21 promotes Cytoskeleton remodeling and stimulates HCC metastasis by inhibiting FLNA ubiquitination and degradation via HSP90α recruitment. Our results position ARHGAP21 as both a potential prognostic marker and a promising therapeutic target in HCC.

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