BACH1 promotes lactate metabolism by transcriptionally upregulating LDHA and MCT4 expression to inhibit ferroptosis in intrahepatic cholangiocarcinoma cells

Ferroptosis is an iron-dependent, non-apoptotic form of cell death induced by the accumulation of lipid peroxidation products. It is involved in cisplatin-induced tumor cell death and plays a dual role of "synergistic enhancement" and "resistance regulation". Furthermore, ferroptosis enhances anti-tumor activity through mechanisms similar to those of cisplatin. Activation of the ferroptosis defence system in tumor cells may cause cisplatin resistance. Cisplatin is a first-line chemotherapeutic agent for intrahepatic cholangiocarcinoma (ICC); however, drug resistance impairs its efficacy. Therefore, exploring ferroptosis-related factors in ICC may help address cisplatin resistance. Moreover, these factors may serve as novel therapeutic targets. We identified BTB and CNC homology 1 (BACH1) by integrating The Cancer Genome Atlas and Ferroptosis Database datasets. BACH1 is upregulated in ICC and associated with poor prognosis. It promotes ICC progression and binds t lactate dehydrogenase A and monocarboxylate transporter 4 promoters to enhance lactate metabolism. Lactate, a crucial downstream effector, can impede ferroptosis through various mechanisms, such as modulating intracellular iron levels, boosting antioxidant system efficacy, and repressing key ferroptosis executor molecules. Additional investigations confirm that BACH1 specifically mitigates cisplatin-triggered tumor cell death by regulating the "BACH1-LDHA/McT4-lactate metabolism-ferroptosis inhibition" axis, leading to cisplatin resistance in ICC cells. Our findings revealed that through this regulatory axis, BACH1 induces cisplatin resistance and may serve as a therapeutic target in ICC.