A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

Abstract

The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

The multifaceted role of ferroptosis in liver disease

“…It should be noted that a recent study found that sorafenib was not a bona fide inducer of ferroptosis based on screening results using a panel of cancer cell lines [ 98 ]. Another recent study found that LIFR (leukemia inhibitory factor receptor) sensitized HCC cell lines to sorafenib-induced ferroptosis both in vitro and in vivo, whereas loss of LIFR expression confers resistance to sorafenib-induced ferroptosis [ 99 ]. These contradictory results might be attributed to different cellular contexts such as the expression levels of LIFR and/or other undefined genes/pathways related to the sensitivity of sorafenib.…”

Solamargine induces hepatocellular carcinoma cell apoptosis and autophagy via inhibiting LIF/miR-192-5p/CYR61/Akt signaling pathways and eliciting immunostimulatory tumor microenvironment

“…Hepatocellular carcinoma (HCC) is well-known to be a malignant cancer and highly effective therapeutic drugs or approaches are insufficiency [ 1 , 2 ]. Of note, Solanum nigrum L .…”

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

“…The way in which to sensitize therapy-resistant cancer cells to ferroptosis remains one of the most important questions that needs to be addressed. Very recently, Yao et al showed that the loss of the tumor suppressor gene encoding leukemia inhibitory factor receptor (LIFR) confers resistance to ferroptosis-inducing drugs through upregulation of iron-sequestering cytokine lipocalin-2 (LCN2) [240]. Therefore, anti-LCN2 therapy using LCN2-neutralizing antibody could be used in combination with sorafenib to improve liver cancer treatment by targeting ferroptosis.…”

“…Therefore, anti-LCN2 therapy using LCN2-neutralizing antibody could be used in combination with sorafenib to improve liver cancer treatment by targeting ferroptosis. Additionally, there are hints that this may have the potential to sensitize tumors to radiation, which requires further investigation [240].…”

“…The growing knowledge of ferroptosis regulators has not been translated into clinical benefits as most of them have been tested only on cell-line models, which are limited in translating therapy response to in vivo settings of patients [240]. Although ferroptosis research is mainly still ongoing in the preclinical phase, the future options are endless, and clinical trials may pave the way to become a prominent therapeutic utility in liver cancer treatment.…”