A Lactic Acid-Chac1 Axis Regulates Ferroptosis-Associated Cell Death and Tumor Progression [A549_LAC RNA-seq]

Tumor metabolic reprogramming plays a critical role in cancer progression, yet the direct involvement of lactic acid in regulating tumor cell death remains incompletely understood. In this study, we identified lactic acid as a previously underappreciated regulator of tumor cell fate and investigated whether lactic acid induces ferroptosis-associated cell death in tumor cells. Lactic acid suppressed tumor cell viability in a dose-dependent manner across multiple tumor cell lines and triggered cell death with both apoptotic and non-apoptotic features. Transcriptomic analysis revealed significant enrichment of ferroptosis-related pathways, accompanied by glutathione depletion, Gpx4 downregulation, and increased oxidative stress. Pharmacological inhibition using Ferrostatin-1 and genetic modulation of Slc7a11 supported the involvement of ferroptosis 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 while promoting tumor growth and metastasis in vivo. Furthermore, Chac1 deficiency was associated with enhanced metastatic progression, suggesting that suppression of ferroptosis may facilitate tumor progression, at least in part, potentially associated with alterations in tumor immune cell infiltration. Collectively, these findings uncover a previously unrecognized link between lactic acid and ferroptosis, establish Chac1 as a critical regulatory node, and highlight the therapeutic potential of targeting the lactic acid-Chac1-ferroptosis axis in cancer treatment.