ESR1-dependent suppression of LCN2 transcription reverses autophagy-linked ferroptosis and enhances sorafenib sensitivity in hepatocellular carcinoma.

Abstract

Sorafenib resistance is a significant hurdle in the treatment landscape of hepatocellular carcinoma (HCC). Lipocalin 2 (LCN2), a secretory glycoprotein that transports lipophilic molecules across cell membranes, is thought to affect the s therapeutic efficacy of sorafenib. Despite its importance, the detailed regulatory pathways involving LCN2 are still being deciphered. We probed the correlation between LCN2 expression and sorafenib resistance in HCC cells. Through the modulation of LCN2 levels, we investigated its role in cell proliferation, apoptosis, and its regulatory effects on autophagy-driven ferroptosis. With the aid of hTFtarget and JASPAR databases, ESR1 was pinpointed as a transcriptional inhibitor of LCN2. The impact of the ESR1-LCN2 axis on sorafenib resistance in HCC was then examined in vitro and validated in a xenograft tumor mouse model. In HCC cells, elevated LCN2 levels were found to be associated with resistance to sorafenib. Depletion of LCN2 resulted in attenuated HCC cell growth and elevated rates of apoptosis and ferroptosis. Overexpression of LCN2 had the opposite effect, promoting cell proliferation and suppressing cell death pathways, a response that could be overridden by autophagy agonists. ESR1 suppressed LCN2 transcription, which in turn activated autophagy-mediated ferroptosis, mitigating sorafenib tolerance in HCC and enhancing the therapeutic index. ESR1 targets LCN2 transcription to initiate autophagy-driven ferroptosis, thereby reducing sorafenib resistance in HCC cells.