CLIC3 promotes lung cancer cell proliferation by regulating intracellular chloride and ROS levels.

Authors

Xiaohui Zhang, Haoyang Qiao, Xingjie Ma, Yali Diao, Qingtong Shi

Published in

Gene. Pages 150359. Aug 16, 2026. Epub Aug 16, 2026.

Abstract

Lung cancer is one of the most prevalent and lethal malignancies worldwide, ranking among the leading causes of cancer-related morbidity and mortality. Uncontrolled cellular proliferation constitutes its central pathological hallmark, underscoring the critical need to identify novel, druggable therapeutic targets. Recent studies have demonstrated that chloride intracellular channel 3 (CLIC3), a multifunctional protein exhibiting both ion channel activity and oxidoreductase function, may play pivotal roles in tumorigenesis. However, its functional significance in lung cancer remains poorly understood. Here we found that CLIC3 was significantly upregulated at both mRNA and protein levels in lung cancer tissues, and its high expression was closely correlated with poor patient prognosis. To elucidate the biological role of CLIC3 in lung cancer pathogenesis, we performed genetic knockdown of CLIC3 in multiple lung cancer cell lines. Silencing CLIC3 markedly impaired tumor cell proliferation, migration, and invasion in vitro. Mechanistically, CLIC3 depletion attenuated chloride efflux and induced substantial accumulation of intracellular reactive oxygen species (ROS). Transcriptomic profiling further indicated that knockdown of CLIC3 may repress lung cancer cell proliferation, at least in part, by inhibiting the C4-dicarboxylate transport pathway. Consistent with these in vitro findings, in vivo xenograft models confirmed that CLIC3 ablation significantly inhibits lung tumor growth. In summary, our study demonstrated that CLIC3 as a critical regulator of lung cancer progression, acting through coordinated modulation of intracellular chloride dynamics and ROS balance. These findings position CLIC3 as a promising prognostic biomarker and a compelling novel therapeutic target for lung cancer.

PMID:
42604641
Bibliographic data and abstract were imported from PubMed on 17 Aug 2026.

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