ACSL4-dependent ferroptosis does not represent a tumor-suppressive mechanism but ACSL4 rather promotes liver cancer progression

Abstract

Ferroptosis is a novel type of programmed cell death that differs from apoptosis in that it involves iron-dependent peroxidation of membrane phospholipids. Its role in a variety of human disorders, including cancer has been hypothesized in recent years. While it may function as an endogenous tumor suppressor in a variety of cancers, its role during initiation and progression of liver cancer, particularly hepatocellular carcinoma (HCC), is yet unknown. Because HCC is most commonly found in chronically injured livers, we utilized two well-established mouse models of chronic injury-dependent HCC formation: Treatment with streptozotocin and high-fat diet as metabolic injury model, as well as treatment with diethylnitrosamine and carbon tetrachloride as toxic injury model. We used mice with hepatocyte-specific deletion of Acsl4, a key mediator of ferroptosis, to explore the significance of ferroptotic cell death in hepatocytes, the cell type of origin for HCC. Surprisingly, preventing ferroptotic cell death in hepatocytes by deleting Acsl4 does not increase the formation of HCC. Furthermore, Acsl4-deficient livers display less fibrosis and proliferation, especially in the HCC model of toxic damage. Intriguingly, in this model, the absence of ACSL4-dependent processes such as ferroptosis significantly slow down the growth of HCC. These findings suggest that during HCC formation in a chronically injured liver, ferroptotic cell death is not an endogenous tumor-suppressive mechanism. Instead, we find that ACSL4-dependent processes have an unanticipated cancer-promoting effect during HCC formation, which is most likely due to aggravated liver damage as demonstrated by increased hepatic fibrosis. Previous studies suggested that ferroptosis might have beneficial effects for patients during HCC therapy. As a result, during HCC progression and therapy, ferroptosis may have both cancer-promoting and cancer-inhibitory effects, respectively.

The regulation and functions of ACSL3 and ACSL4 in the liver and hepatocellular carcinoma

“…However, the association between ACSL4-induced tissue damage and HCC is likely to more nuanced because in a diethylnitrosamine carbon tetrachloride, chemically induced liver injury disease model, there was increased hepatic fibrosis when ACSL4 was expressed, and under such circumstances, there was also a subsequent increase in tumour progression which manifested as larger tumours. 127 These results are noteworthy since they demonstrate that at least in these experimental models, ACSL4-dependent ferroptosis during liver injury neither initiates nor suppresses the formation of HCC but may increase tumour progression in instances where ACSL4-dependent cell death leads to fibrosis. Furthermore, the authors also considered that the effects of ACSL4 on tumour growth might be mediated through functions other than ferroptosis such as upregulated lipid metabolism, which would align with other recent work in this area.…”

“…In adrenocortical tumour cells, ACSL4 can undergo hormone-induced phosphorylation 123 and there is now a precedent for ACSL4 activation by phosphorylation catalysed by PKCβII during ferroptosis 61 -a process likely to be relevant for precancerous liver disease. 127 Another recently described post-translational modification of ACSL4 with potential relevance to hepatocarcinogenesis is its O-GlcNAcylation catalysed by N-acetylglucosaminyltransferase, and this is associated with ACSL4-upregulated mTOR signalling. 37 Elevated protein O-GlcNAcylation is associated with increased oncogenesis in HCC and is thought to result from aberrant glucose metabolism (eg, see [158][159][160][161] ).…”

“…71 It is not yet known if HCC cells are similarly susceptible to this mode of T-cell-induced cell death but there has been significant research, and indeed some debate, 56 into the induction of ACSL4-dependent ferroptosis as a potential anti-tumour strategy for HCC 32,33,177 ; or alternatively, direct inhibition of ACSL4 to block its tumour-promoting functions that do not involve ferroptosis. 16,31,37,55,127 There is less literature available on the role of ACSL3 in pathological steatosis. There has been some speculation that ACSL3 may play a protective role in NAFLD based on its upregulation in response to oncostatin M 48,51 -a member of the interleukin (IL)-6 family of cytokines implicated in post-injury liver tissue regeneration.…”

NAT10, an RNA acetyl cytidine transferase restrains ferroptosis in cancer cells by maintaining SLC7A11 RNA stability

“…The question is whether other available fatty acyl CoA enzymes are involved in the formation of PUFA-CoA in NAT10 KD cells. Recently, it was reported that ACSL4 promotes cancer progression and therefore ACSL4-dependent ferroptosis does not necessarily represent tumor suppression (38). Another study challenges the current view of ACSL4 as the universal ferroptosis regulator for the following reasons ferroptosis is mostly induced in GPX4-dependent inhibition using RSL3, however, SLC7A11 inhibition with erastin or cystine starvation induces ferroptosis either from GPX4-dependent or GPX4-independent mechanisms, this is because the cystine uptake is not only important for glutathione synthesis but also biomolecules such as coenzyme A (CoA) (39,40).…”

Physiological Effects of Ferroptosis on Organ Fibrosis

“…In contrast, a recent study found that an ACSL4-dependent process plays an unexpected cancer-promoting role in HCC formation. In an HCC model of chronic liver injury, loss of 5 Oxidative Medicine and Cellular Longevity ACSL4 significantly impaired the progression of tumor growth, accompanied by lower levels of tissue fibrosis and proliferation [53]. ACSL4-dependent ferroptosis establishes a link between tissue fibrosis and tumor progression, and hepatocyte ferroptosis is a breakthrough target that aggravates fibrotic and proliferative events as a promoter of HCC growth.…”