Authors
Lilan He, Jiali Chen, Aaron Qi Zhang, Rui Wu, Shitong Zhong, Siyu He, Jingyuan Lu, Bin Shao, Fan Hu, Jiayun Yu, Hanwen Li
Published in
Pathology, research and practice. Volume 287. Pages 156665. Aug 17, 2026. Epub Aug 17, 2026.
Abstract
Tumor metabolic reprogramming plays a critical role in cancer progression, but how lactic acid influences tumor cell death remains incompletely understood. In this study, we investigated whether lactic acid induces ferroptosis-associated cytotoxicity and examined the underlying role of Chac1. Across multiple tumor cell lines, lactic acid reduced cell viability in a dose-dependent manner and induced cell death with both apoptotic and non-apoptotic features. These effects were not solely attributable to extracellular acidification. Transcriptomic analysis of LL2 cells revealed enrichment of ferroptosis-related transcriptional signatures, accompanied by glutathione (GSH) depletion, GPX4 downregulation, and increased oxidative stress. Treatment with Ferrostatin-1 and genetic targeting of Slc7a11 supported the involvement of ferroptosis-associated mechanisms in lactic acid-induced cytotoxicity. Mechanistically, we identified Chac1 as an important mediator linking lactic acid-induced metabolic stress to ferroptosis-associated tumor cell death, as Chac1 knockdown attenuated cytotoxicity in vitro. Furthermore, Chac1 knockdown promoted tumor growth and lung metastasis in vivo, supporting the tumor-suppressive role of Chac1 in these models. Collectively, these findings uncover a link between lactic acid and ferroptosis-associated tumor cell death, identify Chac1 as an important mediator of this response, and support a tumor-suppressive role for Chac1 in vivo.
PMID:
42632256
Bibliographic data and abstract were imported from PubMed on 23 Aug 2026.
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