ARHGAP40 suppresses clear cell renal cell carcinoma progression and is associated with altered glutamine-related metabolism and redox balance.

Authors

Na You, Xiaoxia Wang, Caizhu Wang, Long Ma, Yanli Lyu, Han Liu, Fan Yang, Jiandong Wang, Longjiang Zhang, Jufang Wang

Published in

Cancer biology & therapy. Volume 27. Issue 1. Pages 2746137. Dec 31, 2026. Epub Oct 08, 2026.

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by marked molecular and metabolic heterogeneity. This study investigated the functional role of ARHGAP40 in ccRCC and examined signaling and metabolic changes associated with ARHGAP40 expression.
TCGA-KIRC and DiseaseMeth datasets were used to analyze ARHGAP40 expression and promoter methylation. Gain- and loss-of-function experiments evaluated malignant phenotypes in vitro, and an ARHGAP40-overexpression xenograft model was used to assess tumor growth. Co-immunoprecipitation and RhoA activity assays assessed ARHGAP40-RhoA interaction and RhoA activation, while PI3K/AKT signaling, glutamine metabolism, GSH/GSSG, and ROS levels were examined. Rescue experiments were performed using SC79, RhoA-Q63L, and NAC.
ARHGAP40 was downregulated in ccRCC and was associated with increased promoter methylation. ARHGAP40 overexpression suppressed cell proliferation, migration, invasion, EMT, and xenograft growth, while promoting apoptosis and G1-phase arrest; ARHGAP40 knockdown produced the opposite effects. Mechanistically, ARHGAP40 was associated with RhoA, and its overexpression was accompanied by reduced RhoA activity and PI3K/AKT phosphorylation. ARHGAP40 overexpression also reduced intracellular glutamine and glutamate levels and net glutamine consumption, decreased the GSH/GSSG ratio, and increased ROS levels. SC79 and RhoA-Q63L partially reversed the biological and redox effects induced by ARHGAP40 overexpression, whereas NAC reversed the redox changes.
ARHGAP40 acts as a tumor suppressor in ccRCC. Our findings support a functional link between ARHGAP40, RhoA-PI3K/AKT signaling, glutamine-related metabolism, and cellular redox balance.

PMID:
42848714
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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