A lactic acid-Chac1 axis regulates ferroptosis-associated cell death and tumor progression.

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.