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

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.